Natural History of HIV

Mark Kelly : Armidale Rural and Referral Hospital, NSW
Rajesh Varma : Sydney Sexual Health Centre, Sydney NSW

Transmission

Human immunodeficiency virus (HIV) is transmitted   following   contact   with   infected   bodily fluids. The typical routes of transmission are unprotected sex, blood-to-blood contact (including needle-stick injuries, sharing injecting equipment and contaminated blood products) and vertical transmission (from mother to child before, during and after birth). Less common routes include tattooing, organ and tissue transplantation, artificial insemination and semi-invasive medical procedures.  The most common mode of HIV transmission is sexual transmission at the genital mucosa accounting for 75-85% of cases worldwide. The probability of HIV transmission per episode of exposure varies (Figure 1). The risk of transmission per exposure may be influenced by factors such as co-existent genital ulcer disease, type of sexual act, vaginal flora, age, genetic factors and stage of HIV disease of the index case.[1]  There is a disproportionate role of the acute infection period in HIV transmission - estimated that transmission from a person with HIV infection acutely accounts for more than 34-50% of cases of newly-acquired HIV.[2]  

 

Sexual transmission of HIV

Biological features

There   are   four   basic   steps   in   the   sexual   transmission   of HIV: 

  • Contact with mucosal epithelium 
  • Uptake by dendritic cells  (DCs)
  • Transport to secondary lymphoid organs
  • Infection of CD4+ cells in secondary lymphoid organs. 

Following mucosal contact, HIV breaches the mucosal barrier, most likely following microtrauma, and is captured by DCs in the lamina propria. DCs are antigen-presenting cells that initiate adaptive immune responses by presenting antigens to and activating CD4+ T cells. After capturing micro-organisms that enter mucosal tissues, DCs migrate to secondary lymphoid organs where they present microbial antigens to resting lymphocytes. During this early phase of HIV infection, viruses use both CD4 and CCR5 receptors to enter cells and differ from other variants in envelope properties, such as glycosylation and susceptibility to interferon α, suggesting a selective advantage of founder viruses for conditions at the mucosal surface.[3]

Attachment of HIV to DCs occurs via binding of HIV envelope proteins to a family of molecules called C-type lectin receptors, which include DC-specific ICAM-3-grabbing non-integrin (DC- SIGN), mannose receptors and langerin. Each of these molecules can bind gp120, and they are expressed on different subtypes of DC. [4], [5]Among their many roles, DCs act as vehicles to transport HIV to secondary lymphoid organs where they hand over HIV to susceptible lymphocytes. Furthermore, DCs present HIV antigens to activated CD4+ T cells. This potentiates both the infection of and replication in CD4+ T cells.[6] DCs express CD4 and CCR5 receptors,[7] but not CXCR4. [8] This may contribute to other factors leading to the preferential sexual transmission of R5 viral isolates.[9] Early simian immunodeficiency virus (SIV) infection is also associated with massive depletion of CCR5 expressing activated CD4 + T cells from the gastrointestinal tract. [10], [11]

Host determinants of HIV transmission

HIV transmission efficiency depends on the inoculum from the person with the infection, and the susceptibility of the exposed person. 1 The most important factor that increases the risk of sexual transmission of HIV-1 is the number of copies per millilitre of plasma HIV-1 RNA (viral load), with a 2·4 times increased risk of sexual transmission for every 1 log10 increase.19 Acute HIV infection, which causes very high plasma viral loads in the first few months, is an important driver of HIV epidemics.20 A reduction in plasma viral load of 0·7 log10 is estimated to reduce HIV-1 transmission by 50%.[12]

The relationship between increased risk of HIV transmission per coital act and increased plasma HIV viral load is greatest in subjects under the age of 35 years.[13] These studies13 support previous observations that people with primary and late-stage HIV infection are more likely to transmit HIV when viral load is high.[14] Plasma HIV viral load usually correlates with HIV viral load in genital secretions.[15] Like plasma HIV viral load, genital HIV viral load is high during the acute primary illness and during late stages of HIV infection. Other host factors that influence HIV transmission are listed in Table 1.

 

 Table 1 Biological factors affecting sexual transmission of HIV
 Factors increasing transmission risk  Index  Recipient
 Plasma viral load  √  N/A
 Sexually transmissible infections  √  √
 Foreskin[16]  √  Increased risk for recipient
 Menstruation [17]   √  √
 Bleeding during intercourse[18]  √  √
 Genital tract trauma  √  √
 Intrauterine device [19]   –  √
Medroxyprogesterone[20]    –  √
Bacterial vaginosis[21]  –  √
Factors decreasing transmission risk
 CCR5 ∆32 homozygosity  –  √
Barrier contraception
N/A = not applicable
Reference:  Adapted  from  Royce  RA,  Sena  A,  Cates W,  Jr.,  Cohen  MS.  Sexual transmission of HIV. N Engl J Med 1997;336:1072-8.

 

The sustained suppression of HIV-1 in genital secretions resulting from antiretroviral therapy (ART) is the most likely mechanism for the prevention of HIV-1 transmission that was observed in serodiscordant couples with HIV-1 infection in the seminal HPTN 052 clinical trial.[22] Studies of HIV sequences during acute and early infection suggest that there is a bottleneck in the virus population during transmission, regardless of route of transmission. In contrast to the extensive sequence diversity present during chronic infection, the sequence diversity in acute infection is much more limited: typically only one or a few genetic variants of HIV can be detected. [23]

Role of sexually transmissible infections

Transmission and acquisition of HIV may be increased in patients   with   concurrent   sexually   transmissible   infections (STIs). Concurrent STIs also have a strong epidemiological link with increased risk of HIV acquisition. Two of the best described STIs that increase HIV risk are herpes simplex virus 2 (HSV-2) and human papilloma virus (HPV); each has been associated with a 2–3 fold increased rate of HIV acquisition in large meta-analyses.[24]

Ulcerative STIs are associated with increased transmission of  HIV.[25]  Both  symptomatic  and  asymptomatic  STIs  increase genital  HIV  viral  load  and  the  numbers  of  cells  within  the genital   tract expressing CCR5.[26]. [27], [28]  Mathematical    models suggest that intercurrent  STIs may increase the likelihood of HIV transmission ten fold.[29]  Treatment of STIs has been associated with  declines  in  genital  HIV  viral  load  to  baseline  levels.[30] These  observations  may  explain  the  dramatic  reductions  in HIV transmission observed following the treatment of STIs and provision of clinical support.[31]

There is epidemiological evidence and biological plausibility to support an association between prevalent HSV-2 and HIV acquisition in both men and women.[32] HSV-2 was found to have the strongest association with HIV acquisition in high-risk women in Tanzania compared with other STIs.[33] The relative risk of HIV acquisition was higher for incident than for prevalent HSV-2 in this study. Valacyclovir has been demonstrated to decrease plasma, vaginal and rectal HIV viral load in individuals with both HIV and HSV2.[34], [35] However, two large randomised trials failed to show a reduction in HIV acquisition in people who received acyclovir to prevent HSV-2 recurrences.[36] Randomised trials of treatment of bacterial STIs also did not show a reduction in HIV transmission.[37] There is no convincing evidence to date that treatment of STIs results in prevention of HIV at the population level.[38] Further studies are awaited to determine if the treatment of STIs will have any real impact on HIV transmission.

The role of circumcision

Male   circumcision   has   a   profound   effect   on   the   risk   of acquisition of HIV in heterosexual couples. Several large randomised prospective studies performed in Africa have shown  a  70%  reduction  in  risk  of  HIV  acquisition  following circumcision.[39][40] However, the role of male circumcision in prevention of HIV in men who have sex with men remains to be determined. Although male circumcision clearly reduces STIs among heterosexual men, its effects among men who have sex with men are unclear. Observational studies of men who have sex with men have reported conflicting levels of association with HIV acquisition. A meta-analysis incorporating more than 50,000 men who have sex with men did not find an association between HIV status and being circumcised (OR 0.95, 95% CI 0.81–1.11)[41] However, the role of male circumcision in prevention of HIV in men who have sex with men remains to be determined. Although male circumcision clearly reduces STIs among heterosexual men, its effects among men who have sex with men are unclear. Observational studies of men who have sex with men have reported conflicting levels of association with HIV acquisition. A meta-analysis incorporating more than 50,000 men who have sex with men did not find an association between HIV status and being circumcised (OR 0.95, 95% CI 0.81–1.11)[42]  

HIV superinfection

Infection   with   two   different   HIV   isolates   is   possible.   HIV superinfection occurs when a person with HIV infection acquires a second viral strain. In contrast, HIV  co-infection  refers  to the situation where two  viral  strains  are  present  at  the  time of initial infection.[43] Dual HIV infection collectively refers to both HIV superinfection and co-infection.[44] Dual infection is a prerequisite for recombination events, which occur between isolates from different HIV subtypes resulting in circulating recombinant forms of HIV (see Basic Virology and immunology -  The taxonomy of HIV and the primate immunodeficiency viruses).

Cases of superinfection have been reported in a variety of situations including intersubtype;[45] intrasubtype;[46] wild-type with drug resistant;[47] drug-resistant with wild-type;[48] and  R5 only with dual tropic.[49] Recombination of superinfecting viruses has been documented in people with chronic  infection. This has involved intersubtype recombination[50] and intrasubtype recombination involving multiclass drug resistant viruses.[51]The exact incidence of superinfection is at present unknown. Cohort based studies have reported that superinfection occurs in 0-5% of patients with HIV.[52], [53], [54], [55], [56]   

The consequences of superinfection are unknown for the individual and also HIV vaccine development. The implication is that the natural immune response to HIV infection is frequently not sufficient to provide protection from infection with another HIV variant, raising concerns for vaccine design.[57] Case reports have associated superinfection with accelerated clinical and surrogate marker progression.[58], [59]  Superinfection with a drug resistant strain  has been  associated with  impaired virological responses to ART.[60] However, not all cases of superinfection have been associated with poorer outcomes as this process has been documented in two patients with long-term non-progressive HIV disease.[61] Studies have been unable to distinguish between co-infection and superinfection; however, they have consistently associated dual infection with higher viral load set points.[62],[63] On balance, evidence suggests that superinfection may have deleterious effects on HIV disease progression. It is not clear if superinfection itself leads to accelerated disease progression, or if unidentified host factors contribute to the accelerated disease progression independent of superinfection.

It is unknown if all patients are at risk of HIV superinfection or when this is most likely to occur. However, superinfection has been documented to occur up to 12 years after initial infection.[64], [65], [66], [67] To date, no case of superinfection has occurred  in  people  taking  ART.[68], [69] However, methods  used  in  these  studies  may  underestimate  the  true prevalence of superinfection. Case reports of superinfection with multiclass resistant HIV potentially suggest that even patients on ART may be at risk of superinfection.[70]

Mother-to-child transmission of HIV infection

Mother-to-child transmission of HIV infection can occur antepartum, intrapartum and postpartum via breastfeeding.  Most cases of mother-to-child transmission occur during labour.  As with sexual transmission, R5 viruses are more likely to be transmitted from   mother   to   child.[71]The mechanisms underlying these observations are not completely defined. The overall risk of vertical transmission of HIV is 25-30%. As for sexual transmission, maternal HIV viral load is the predominant risk factor for vertical transmission.[72] However, HIV transmission can occur despite low maternal HIV viral load.[73] Mothers with plasma HIV viral load less than 1000 copies/mL have transmitted HIV to their infants. The prime determinant of transmission, in this context, is absence of maternal ART. Transmission of HIV from mother to baby occurs in 10% of mothers not receiving ART  with  low  HIV  viral  load  compared  with less than 1% of mothers on ART.[74]  There is an increased risk of transmission either perinatally or postnatally when women contract HIV during pregnancy.

Other factors associated  with  an   increased  risk   of perinatal  HIV  transmission   include low maternal CD4+ T cell count, prolonged rupture of membranes,   pre- term  labour, chorioamnionitis, cigarette smoking or illicit drug use  during  pregnancy,  and  obstetric procedures such as amniocentesis and amnioscopy. Caesarean section before the onset of labour significantly reduces the risk of HIV transmission,[75] although ART is the mainstay of HIV prevention and there is no additional benefit of caesarean sections in women receiving effective ART with an undetectable maternal HIV viral load at the time of delivery.

Breastfeeding approximately doubles the risk of mother-to-child transmission of HIV and accounts for approximately one third of cases of mother-to-child transmission.[76], [77] High levels of HIV in breast milk cells correlate with increased risk of transmission. Avoidance of breastfeeding has been suggested to reduce the risk of HIV transmission.[78] However, in resource-poor settings, breast milk substitutes may be difficult to obtain and benefits may be off-set by increased respiratory and gastrointestinal infections in non-breastfed infants. Exclusive breastfeeding carries a lower risk of HIV transmission than mixed feeding in South Africa.[79] Other factors which increase the risk of postnatal HIV transmission include maternal nipple lesions, mastitis, low maternal CD4+ T cell count, infant oral thrush and breastfeeding for longer than 15 months.[80]

Chemokine genetic polymorphism influences the rate of mother-to-child transmission of HIV. Maternal  heterozygosity for genotype SDF-1-3`A is associated with almost double the risk of transmission of HIV, independent of maternal plasma HIV viral load.[81] Infant chemokine genetic polymorphism has not been demonstrated to influence HIV acquisition rates.

HIV transmission by other bodily fluids

The  risk  of  HIV  transmission  by  oral  sex  and  kissing  is  low. While infectious HIV is detected in the saliva, it is present in substantially reduced quantities compared with blood or genital secretions. Furthermore, the saliva contains endogenous antiviral factors including HIV-specific antibodies and a number of soluble factors such as secretory leukocyte protease inhibitor.[82] Saliva may alter gp120 structure and lyse HIV-infected cells secondary to the inherent hypotonicity of the saliva. While oral sex has been identified as the only reported risk factor in some patients,[83] the likelihood that oral sex is an important transmission route of HIV is low. The low risk of HIV transmission via orogenital sex is supported by a large cohort study in which no case of HIV transmission was identified  in more than 210 person-years follow-up  in a cohort of HIV-discordant couples who engaged in protected anal or vaginal sex but unprotected oral sex  without  other  risk  factors  for  HIV.[84] However,  oral transmission of SIV has been reported in a macaque model.[85] There is no evidence that HIV transmission can occur as a result of exposure to tears, sweat, faeces or urine.

Disease progression

Phases of HIV disease

HIV disease is characterised by three phases: acute primary illness, asymptomatic chronic illness and symptomatic chronic illness. The rate of progression from one phase to another is highly variable.

Following transmission, HIV initially replicates in regional lymph nodes. This results in a rapid rise in plasma HIV viral load to levels in excess of one million copies/mL. This phase is accompanied by dissemination of HIV to lymphoid organs, gut and genital tract.[86] Following the peak in viraemia, plasma viral load decreases co-incident with the development of host cellular immune responses.[87] The peak in plasma HIV viral load and development of cellular immune responses is associated with a symptomatic illness in 60-90% of patients.[88], [89]

The following features of the acute primary illness of HIV are associated with poorer prognosis:

  • symptomatic primary illness[90]
  • longer duration of acute primary illness[91], [92]
  • neurological symptoms[93]
  • presence of oral candidiasis[94]
  • greater number of signs and symptoms[95]
  • greater severity of symptoms.

The following laboratory markers have been associated with poorer prognosis during acute primary illness of HIV:

  • baseline CD4+ T cell count [96]
  • baseline HIV DNA level [97]
  • slow decay of plasma HIV viral load.[98]

While the peak HIV viral load during acute primary illness is not predictive of HIV disease progression, it is associated with severity of symptoms, which has been linked to a poorer prognosis.[99]The acute primary illness generally resolves spontaneously within 14 days.[100]

On resolution of the acute primary illness, the patient enters a prolonged, clinically asymptomatic period. Nevertheless, virological and immunological progression occurs during this period, driven by immune dysfunction and immune activation. Progressive, subclinical, HIV-induced immunopathology results in the development of symptomatic HIV disease. Symptomatic HIV disease is divided into two phases that are not necessarily contiguous: acquired immune deficiency syndrome (AIDS) and symptomatic HIV infection (non-AIDS).  Patients may present with an AIDS-defining illness without preceding HIV-related symptoms. Symptomatic non-AIDS events are markers of clinical immunodeficiency and predict progression to AIDS.[101]

Rates of disease progression

The rate of disease progression is highly variable among individuals, ranging from 6 months to more than 20 years. In the absence of treatment the median time to develop AIDS is 10-11 years.[102], [103] The median survival following AIDS in the absence of ART is dependent on the CD4+ T cell count at AIDS diagnosis: 3.7 years if the CD4+ T cell count is less than 200 cells/μL and 1.3 years if the CD4+ T cell count is less than 70 cells/μL.[104] However, rates of disease progression to AIDS vary from rapid progression within 6 months of seroconversion,[105] to no significant progression. Individuals with no disease progression were previously referred to as long-term non-progressors (LTNP). By definition, these patients had CD4+ T cell counts above 500 cells/μL and were asymptomatic despite more than 10 years of infection without specific anti-HIV therapy. Between 1-5% of people with HIV infection fall into this category.[106] These estimates are complicated by the fact that there is no standardised definition of a LTNP, and thus definitions used (and the way in which they are applied, particularly in the presence of varying follow-up and irregularly measured CD4+ T cell counts) are not consistent [107]. However, with longer follow-up and the use of improved prognostic models, these people do eventually experience HIV disease progression suggesting that rather than representing a distinct group of HIV-positive individuals, LTNP are more likely to represent individuals at one tail end of a normal distribution curve. [108]

The term elite controller refers to people who maintain undetectable HIV viral loads in the absence of antiretroviral therapy (See section HIV immunopathology: Immunological control in specific patient groups-Long-term non-progressors and elite controllers).

Approximately 0.6% of people with HIV infection are considered elite controllers.[109] Such people have been shown to have stronger HIV specific immune responses compared with people who do not control viral replication. Genetic factors known to be associated with slow progression of HIV disease were detected in less than 25% of these people;[110] 10% of such people had CD4+ T cell counts  below  350  cells/ml  and 3% had AIDS.[111] Elite controllers had increased plasma levels of lipopolysaccharide associated with increased levels of immune activation when compared with HIV-negative controls.[112] Although there is clearly an overlap between the LTNP and elite controller groups, not all LTNP have a suppressed viral load, and not all elite controllers have high CD4+ T cell counts.

Surrogate markers of disease progression

Laboratory findings, such as falling CD4+ T cell numbers, rising plasma HIV viral load and increasing CD38 expression by CD8 cells, are non-clinical, surrogate markers of disease progression. These markers correspond to fundamental aspects of HIV disease pathogenesis, namely immunodeficiency, viral replication and increased immune activation, respectively.

CD4+ T cell count

 The CD4 cell count was the earliest surrogate marker used in HIV management.[113], [114] Absolute CD4 cell count, CD4 cell percentage and CD4 cell rate of decline have all been demonstrated to predict progression to AIDS.[115], [116]   The risk of development of certain opportunistic infections can be stratified according to CD4 cell count. For instance, the relative risk of development of Pneumocystis jirovecii pneumonia in patients with CD4 cell counts less than 200 cells/μL (14%) is 4.9.[117]

CD4 cell count declines gradually during HIV disease progression. The rate of decline accelerates over time, averaging 80-110 cells/μL per year.[118] Pre-seroconversion host factors such as the amount of T-cell receptor excision circles in CD4 cells predicts subsequent CD4 decline.[119], [120] CD4 cell count is predictive of AIDS progression across all viral load strata, although its predictive value increases with duration of HIV infection.[121], [122]  The CD4 cell count in blood, however, does not reflect total body CD4 cells which predominantly reside in lymphoid tissue. The gut-associated lymphoid tissue is infected early in HIV infection and leads to a dramatic loss in the total CD4+ T pool, which remains depleted throughout the natural history of untreated infection.[123] 

The exact mechanism of the CD4+ T-cell population depletion reflects the balance between de novo production, proliferation, differentiation, and death of thymic emigrants, naive, effector, and memory T cells (This is covered in greater detail in the section on HIV immunopathology).

Plasma viral load

Plasma HIV viral load is predictive of disease progression at all stages of infection and across all CD4+ T cell strata. Early studies suggested that, following an initial peak, during the acute illness of HIV, plasma HIV viral load declined to a setpoint and remained stable during the asymptomatic phases of HIV, and then increased a few  years  before  the  development of AIDS.[124], [125] However, this pattern is not supported by other studies.[126], [127]

Transmission studies assessing the factors associated with HIV viral load setpoint have observed that the HIV viral load in the donor was closely associated with the HIV viral load at presentation in the seroconverting partner.[128] Overall, the HIV viral load setpoint was a function of the source partner HIV viral load, the sex of the seroconverter, the human leucocyte antigen (HLA) class I alleles of the seroconverter, and the sharing of HLA- class I alleles between partners in a transmission pair.[129]

Plasma HIV viral load has also been reported to gradually rise over time and that a setpoint is not reached.[130] In the initial 3 years following seroconversion, HIV viral load changes are apparent only in people who develop AIDS within that period. After this time, HIV viral load changes are detectable; both the HIV viral load rate-of-increase and the absolute value predict an increased progression rate to AIDS.[131] HIV proviral DNA levels in peripheral blood mononuclear cells also predict progression to AIDS independently of both plasma HIV viral load and CD4+ T cell count.[132]

HIV viraemia dynamics and the evaluation of a setpoint require consideration of host and viral genetics. Despite its wide use, there is still no standard method for determining HIV-1 viral load setpoint, with multiple methods and definitions having been used. There has been interest in determining whether HIV has become more virulent in recent years. Large cohort analyses have provided conflicting views based on progression from HIV viral setpoint to CD4+ T cell decline.[133]

CD38 expression on CD8 cells

CD38 is a cell-surface   glycoprotein that is detected   on lymphocytes and natural killer cells. Its expression is increased on activated lymphocytes. Upregulation of CD38 expression by CD8+ T cells during primary HIV illness[134] and other stages of HIV disease [135] is predictive of subsequent decline in CD4+ T cell count.

Furthermore, elevated expression of CD38 by CD8+ T cells late in HIV disease is a strong predictor of disease progression.[136] These observations underscore the importance of immune activation in the pathogenesis of HIV disease.

Other markers of immune activation have also been demonstrated to have prognostic significance in HIV disease progression. Soluble tumour necrosis factor (TNF) receptor is a stronger predictor of progression to AIDS than HIV viral load.[137] Not all markers of CD8+ T cell activation indicate a poor prognosis. Increased expression of HLA-DR in the absence of CD38 is a good prognostic marker.[138]

Interactions between surrogate markers of disease progression

CD38 expression by CD8+ T cells is the strongest single predictive marker of disease progression in all stages of HIV disease,[139] but models which incorporate CD8+ T cell activation, CD4+ T cell count and HIV viral load predict disease progression most accurately.[140] The strength of the predictive associations of the three separate markers changes over time.

In early HIV disease, the best predictive models include only CD38+ CD8+ T cells and HIV viral load, with CD4+ T cell count adding little further predictive power. In contrast, in the absence of data on CD38+ CD8+ T cells, CD4+ T cell count adds to the predictive power of HIV viral load.79In late stage HIV infection, the best predictive models include all three surrogate markers.

These findings are consistent  with  previous  reports stating  that  early  HIV viral  load  predicts  subsequent  CD4+ T cell count decline[141] and that CD4+ T cell count is a stronger predictor of disease progression in late HIV disease when viral load and CD4+ T cell count are used as single markers.[142] However, in patients with a HIV viral load less than 3000 copies/mL (when measured by branched chain DNA assay), CD4+ T cell count is a stronger predictor of disease progression than either HIV viral load or CD38+ CD8+ T cells.[143]

Host factors influencing disease progression

Severity of disease after infection is variable. The majority of knowledge about the impact of host genetic variation on outcome of HIV-1 infection has been gained through studies of historical cohorts collected before the implementation of ART. An impact of host genetic variation on susceptibility to HIV-1 infection was identified early in the pandemic, with a major role attributed to the genes encoding HLA class I and the chemokine receptor CCR5. Many other variants throughout the genome have been claimed to have an association with outcome after HIV-1 infection, but only variation within or near the HLA genes and, to a lesser extent, the CCR5 locus have been replicated in large genome-wide association studies.[144]

Chemokine protein and chemokine receptor polymorphisms

Genetic polymorphisms  of multiple  chemokine receptors, chemokine proteins and related cytokines have been demonstrated to influence both HIV transmission and HIV disease progression (Table 2). The first reported polymorphism of CCR5 was a 32-base-pair deletion (CCR5∆32). This gene polymorphism encodes for a CCR5 molecule that is not expressed on the cell surface. 

 

 Table 2 Chemokine protein and receptor and related polymorphisms known to influence HIV disease 
    Mutation  Influence on natural history   Putative effect
  Site  Codon  Transmission  Disease progression  
Chemokine protein
SDF1 3’UTR SDF1-3A’ Decrease
MTCT[145]
decrease [146]  ? block CXCR4
 RANTES  Promoter  G4 increase [147]  decrease[148]  ? increase RANTES
Chemokine receptor
CCR5  Promoter 59029 G   decrease [149] decreased promoter activity
CCR5P1   increase [150]  
  ORF 59356 T CCR5∆32 increase MTCT decrease[151], [152] decrease[153]  
CCR2 ORF CCR2-64I  

decrease[154], [155]

delayed progression to AIDS then accelerated progression[156]
Linked with CCR5 promoter polymorphism,[157] however  mechanism undefined
Once X4 virus is selected disease progression is accelerated.[158]
Related cytokines
IL-4 Promoter IL-4 589 T   Decrease[159], [160] increased acquisition of X4 phenotype, associated with delayed progression to AIDS and then accelerated progression ? increased IL-4 production with resultant decrease CCR5 and AIDS then increase CXCR4 expression
IL-10 Promoter IL-10 5’A Increase[161] Increase[162] decreased IL-10 inhibition of HIV
IL: interleukin; MTCT: mother-to-child transmission; ORF: open reading frame; RANTES: regulated on activation, normal T cell expressed and secreted; SDF: stromal-derived factor; UTR: untranslated region.

 

The absence of CCR5 is the basis for the resistance of some individuals to infection with HIV-1 that uses CCR5 alone as a coreceptor (so called R5 viruses) FIG NOT INCLUDED (Figure 2).[163] However, homozygotes for CCR5∆32 can occasionally be infected with HIV isolates which use other coreceptors.[164] Cell-surface expression of CCR5 is reduced in   heterozygotes (CCR5∆32/WT) and this is thought to be the basis of delayed progression to AIDS in these subjects. Mutations can also occur in the promoter region of the CCR5 gene. Mutations in CCR2-64I are also associated with delayed disease progression.[165] Another chemokine that binds to CCR5, CCL3 is also relevant to disease progression. Lower CCL3L1 copy number is associated with higher susceptibility to HIV infection and disease progression.[166]

HLA alleles

A  number  of  HLA  alleles  have  been  shown  to  impact  on  the natural history of HIV infection. The following HLA genotypes are associated with decreased rates of disease progression: HLA B27, HLA B51 and HLA B57. People with HLA B57 are less likely to present with acute asymptomatic HIV illness and are more likely to have broader and stronger HLA B57-restricted anti-HIV immune responses.[167] People with HLA B57 who do not maintain HIV specific responses against a specific HIV nef epitope, HW9, are more likely to have progressive disease than HLAB57 people who maintained such responses.[168] However, the precise mechanism(s) that mediate this influence are not fully understood.

Gender differences

Some   studies   have   demonstrated   that   women   develop AIDS at higher CD4+ T cell counts than men.[169] However, this difference may be explained by decreased access to care rather than biological effects. Conversely, other studies have demonstrated that, for a given CD4+ T cell count, women have up to 0.3 log lower plasma HIV viral load than men.[170] This difference is most apparent in the 4 years following seroconversion.[171] After this time, women experience greater rises in plasma HIV viral load. This late rise in HIV viral load in women may account for the lack of gender differences in disease progression observed in other cross-sectional studies.[172] The underlying mechanisms for these observed differences remain undefined. No gender differences have been demonstrated in clinical progression following seroconversion.[173]

Viral factors

Multiple viral factors have been associated with altered HIV disease progression including deletion of certain viral genes; coreceptor usage; viral subtype and replicative capacity. Viral factors which were associated with slower progression rates included attenuated viruses such as nef-deleted isolates.[174] People with dual tropic (or mixed R5 and X4) viral populations progressed to AIDS 3.8 times more rapidly, independent  of CD4+ T cell count and HIV viral load, than those with only R5 isolates at baseline.[175] Viruses, which use the CXCR4 coreceptor, are more pathogenic than other strains: they form syncytia (giant, multinucleated cells) in vitro   and  were  previously  described as syncytium-inducing variants. In contrast, R5 viruses are less pathogenic than X4 viruses: they do not form syncytia in vitro and were previously termed non-syncytium-inducing variants. Transmission of X4 strains, which occurs rarely, is associated with accelerated disease progression. A case of acquisition of a dual tropic, multidrug resistant isolate with high replicative capacity was reported to be associated with rapid disease progression.[176] The viral coreceptor usage changes from R5 to X4 in up to 40% of patients during the course HIV disease. A coreceptor switch changes the viral phenotype and is associated with acceleration in CD4 cell loss and disease progression.[177] Subjects with syncytium-inducing (X4) variants are seven-times more likely to progress to AIDS over a 30-month period. In the 60% of individuals who do not demonstrate a change from R5 to X4, it is unclear why there is accelerated disease progression, but this may be  secondary  to  a  change  in  affinity  for  CD4 or coreceptors.

Some studies report that HIV-1 subtype is an independent predictor of HIV disease progression. Women with the Brazilian variant of subtype B HIV infection had a faster progression of HIV disease than women with other subtype B variants.[178] People with subtype A HIV infection have slower rates of disease progression relative to subtype D and other subtypes.[179], [180], [181] Viral subtypes may also differ in their capacity to be transmitted. Subtype C is associated with increased vaginal shedding.129[182] Viral replication capacity has been shown to be associated with CD4+ T cell decline but not to HIV viral load. People with infection with viruses with high replicative capacity were more likely to have faster rates of CD4+ T cell decline independent of plasma viral load.[183]

GB virus-C

The flavivirus GB virus-C (GBV-C), previously designated hepatitis G, may have a protective effect on HIV disease progression. No human disease has been associated with GBV-C infection.  Epidemiological studies have described an association between GBV-C co-infection and decreased morbidity and mortality in individuals with HIV infection.[184], [185], [186]   People with GBV-C co-infection have reduced mortality, increased survival post-AIDS and lower plasma HIV viral loads compared with people with HIV without GBV-C infection. Increases in CD4+ T cell counts have been demonstrated in some,[187] but not all studies of people with HIV/GBV-C co-infection.[188] As GBV-C and HIV share transmission routes, co-infection is common and has been demonstrated in between 16 - 40% of people with HIV in the USA. This compares with a prevalence of GBV-C in 2% of volunteer blood donors and 20% of intravenous drug users in the USA.[189], [190]

Several mechanisms of interaction between GBV-C and HIV have been proposed, including altered cytokine profile, HIV coreceptor expression, T-cell activation, Fas-mediated apoptosis and direct inhibition of HIV replication.[191] In vitro studies have demonstrated that GBV-C inhibits HIV replication by inducing the production of chemokines, which may inhibit HIV replication and reduce the expression of coreceptors on the surface of T-cell.[192], [193] This is in keeping with the observation that persistent infection is required for delayed progression as people who clear GBV-C infection have higher mortality rates than those with persistent infection.[194] At present a causal relationship has not been proven.

Other predictors of HIV disease progression

Behavioural factors, drug-use behaviour and intercurrent STIs are not associated with an increase in disease progression,[195] although certain behaviours have been associated with a poorer response to combination antiretroviral therapy (cART). The mode of acquisition of HIV infection does not influence HIV disease progression rates.[196]

Serious non-AIDS events

The causes of death in people with HIV infection have shifted from traditional AIDS-related illnesses to serious non-AIDS events since the introduction of ART. The most common of these are: atherosclerotic cardiovascular disease, non-AIDS- defining malignancies, liver disease and renal disease.[197] There is a gradient of risk, which reduces with increasing CD4+ T cell count. Fatal liver disease and fatal non-AIDS malignancies are more common in people with lower CD4+ T cell counts.[198], [199]  However, people with high CD4+ T cell counts remain at risk of serious non-AIDS events. The risk of serious non-AIDS events in people with HIV infection is greater than for people without HIV after accounting for other risk factors such as smoking.

There is evidence that the increased risk of HIV comorbidities are caused by persistent immune activation and inflammation that start early after infection and continue despite effective suppression of HIV replication.[200] Immune activation, as previously described, is a marker of HIV disease progression and a key determinant of CD4+ T cell depletion. People who cease antiretroviral therapy have an increased chance of developing serious non-AIDS events and also experience increased levels of immune activation.[201], [202], [203]

Early randomised data and cohort studies suggest that ART may decrease the risk of serious non-AIDS events in people with CD4+ T counts above 350 cells/μL.[204] The Strategic Timing of AntiRetroviral Treatment (START study) has now shown a similar benefit in commencing ART at CD4+ T counts above 500 cells/ μL in decreasing serious non-AIDS events (SNAE). HIV infection also results in an inflammatory response,   which has been   demonstrated to activate   the coagulation system.[205] Increased D-dimer levels have been related to cardiovascular disease in people without HIV infection and may be relevant to cardiovascular risk in people with HIV infection on cART.[206]

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