Rationale
Antiretroviral therapy alone, by suppressing viral replication, results in marked but incomplete restoration of cell-mediated immunity. Moreover, HIV-specific immune responses decline in people taking cART. In some individuals receiving cART, restoration of total CD4+ T cells is also impaired despite excellent virological control. Current cART strategies are limited by toxicity, cost, adherance, resistance and the need for continuous therapy. The incomplete recovery of cell-mediated immune function following cART is related to: persistent immune activation; loss of HIV-specific immune responses; persistent HIV-induced immunodeficiency; and HIV-associated anergy. Immune-based therapies may prove to be useful adjuncts to cART in augmenting and accelerating improvements in cell-mediated immune function.
The data from the monkey models, including African green and sooty mangabey monkeys, suggest that evolution of host factors has allowed the persistence of SIV as a non-lethal infection.(Broussard et al., 2001) This adaptation seems to have occurred in the presence of high SIV viral load and results in reduced immune activation and apoptotic loss of T cells.(Dunham et al., 2006) Non-immunological factors control retroviral replication, including the APOBEC system and the TRIM5alpha system.(Chiu et al., 2005) These represent innate mechanisms that control retroviral infection including genomic repetitive elements and endogenous retrovirus.(Chiu et al., 2006) A whole genome analysis showed no association with acquisition of HIV other than the effect of CCR5Δ32. (McLaren et al., 2013) By this same approach, disease progression was related most strongly to the well-known HLA-B57 association. The protective change was also linked to an endogenous retroviral element (PC5), an HLA-C related determinant and an RNA polymerase subunit gene.(Fellay et al., 2007)
Therapeutic vaccines for boosting HIV-specific immunity
Strategies to restore and maintain HIV-specific immune responses may be critical in the long-term control of HIV disease. Controversy persists regarding the essential components of the immune responses needed to prevent disease progression or to clear virus in patients on cART, the identity of immunogenic epitopes that will stimulate broad immune responses, and the identity of in vitro correlates of immune protection. The success of boosting HIV-specific immune responses will require the stimulation of both CD4+ T and CD8+ T cell responses; the stimulation of broad responses directed towards multiple epitopes by polyfunctional T cells; and the concurrent use of cART to limit HIV replication. A recent CMV vector vaccine used in SIV infection of non-human primates looks the most promising of the existing vectors.(Hansen et al., 2013)
Approaches to boosting HIV-specific host immune responses by the use of CTL expanded in vitro have been unsuccessful. (Koenig et al., 1995) However, expansion of CTL and CD4+ T cells in vivo using DC vaccination is clearly effective in reducing viral load.(Lu et al., 2004) Simpler therapeutic vaccination strategies that use exogenous or endogenous antigens are being developed. In contrast, the hope that intermittent cessation of cART might potentially regenerate HIV-specific immune responses has been discarded because of the clear reduction in survival and lack of clear efficacy of this strategy. Similar approaches to induce high level neutralising antibody have some potential application. (Yamamoto et al., 2007)
Use of immune modulators, including cytokines, to reduce immune activation and improve CD4+ T cell recovery has had only a modest effect compared to cART and does not have a clear role at present (Tables 2 and 3).
Table 2. Immune modulating cytokines that may have a therapeutic role in HIV management
|
Cytokine |
Immune effect |
References |
|
IL-2 |
Increase HIV-specific responses (CAF) Increase antigen presentation |
(Abrams et al., 2009) |
|
IL-7 |
Increase thymus-mediated T lymphocyte differentiation and homeostatic T cell proliferation Reduced colonic and systemic inflammation |
(Imamichi et al., 2011; Levy et al., 2009) (Sereti et al., 2014) |
|
IL-10 |
Decrease pro-inflammatory cytokine production |
(Villacres et al., 2012; Pott et al., 2007) |
|
IL-12 |
Increase HIV and non-HIV CTL responses |
(Kalams et al., 2013) |
|
IL-15 |
Increase effector memory CD4+ T cells Increase CTL perforin expression Increase T cell replication and virus production |
(White et al., 2007) (Manganaro et al., 2018) |
|
IL-16a |
Increase responsiveness to IL-2 Decreased activation-induced apoptosis |
(Cruikshank et al., 1996; Parada et al., 1998) (Center et al., 2000) |
|
IL-21 |
Increase CTL perforin expression Decrease Treg production by TGF-beta Increase TH17 cells. |
(White et al., 2007; Pallikkuth et al., 2013; Attridge et al., 2012) (Ortiz et al., 2016) |
|
GM-CSF |
Increase macrophage anti-HIV activity Vaccine adjuvant |
(Overton et al., 2014) (Herasimtschuk et al., 2014) |
|
KGF |
Increase production of IL-7 by thymic epithelial cells |
(Jacobson et al., 2014; Herasimtschuk et al., 2013) |
|
Growth Hormone |
Increase thymic tissue Reduction in lipoatrophy. |
(Lindboe et al., 2016) |
|
IFNα |
Reduction in Type I IFN reduces viral load in animal models, though effects of IFN depend on stage of disease in SIV infection |
(Zhen et al., 2017; Sandler et al., 2014) |
a These cytokines also have direct anti-HIV effects as suggested by inhibition of HIV replication in vitro. CAF = cell-associated factor; CTL = cytotoxic T lymphocyte; IL = interleukin; Th1 = type 1 helper, KGF = keratin growth factor; TGF = transforming growth factor.
Table 3. Pharmaceutical agents that decrease immune activation associated with HIV infection
|
Agent |
Mechanism of action and rationale |
References |
|
Corticosteroids |
Decrease pro-inflammatory cytokine production Decrease activation induced lymphocyte death |
(Kasang et al., 2012; Wallis et al., 2003) |
|
Cyclosporin |
Decrease target cells by decreasing IL-2 production, cellular activation and proliferation Decrease viral maturation by interaction with immunophilins |
(Rizzardi et al., 2002; Markowitz et al., 2010; Lederman et al., 2006) |
|
Hydoroxyurea |
Decrease cellular proliferation by decreasing intracellular nucleotide concentration. No clinical benefit. |
(Benito et al., 2007; Bloch et al., 2006) |
|
Mycophenolate |
Decrease lymphocyte proliferation to antigenic stimuli Increase apoptosis of activated lymphocytes |
(Kaur et al., 2006) |
|
Thalidomidea |
Decrease production of TNF-alpha Reduces CCR5 and CXCR4 upregulation by HIV |
(Wohl et al., 2002; Juffermans et al., 2000) |
|
Rapamycin |
Acts through inhibition of mTOR to reduce cell activation, apoptosis and autophagy |
(Nicoletti et al., 2011) |
|
Statins |
Atorvastatin reduces immune activation by decreasing T cell signalling. Pravastatin does not have this effect. |
(Overton et al., 2014; De Wit et al., 2011; Eckard et al., 2014) |
|
Hydroxychloroquine |
Hydroxychloroquine and chloroquine act on TLR signalling in pDC to reduces immune activation. Limited or no effects on CD8+ T cell activation or CD4+ T cell recovery in antiretroviral therapy-treated patients and CD4+ T cell depletion in untreated patients. Prevention of infection by reducing mucosal immune activation |
(Paton NI et al., 2012; Murray et al., 2010)(Routy et al., 2015; Piconi et al., 2011) (Lajoie et al., 2018) |
|
Aspirin |
Reduced inflammation at mucosal surface. reduces HIV infection |
(Lajoie et al., 2018) |
|
Cyclooxygenase-2 (COX-2) inhibitors |
Reduced LPS-induced upregulation of COX-2 |
(Pettersen et al., 2011; Kvale et al., 2006) |
|
Ruxolitinib |
Inhibits cytokine activation by Jak 1,2 inhibition |
(Gavegnano et al., 2017) |
|
Tofacitinib |
Inhibits cytokine expression by Jak1,3 inhibition |
(Gavegnano et al., 2017) |
|
anti-IFNAR |
Reduce type 1 interferon-induced cell death and immune activation |
(Cheng et al., 2017) |
a Because of effects in nucleotides, these agents may augment effects of antiretroviral agents. TNF = tumour necrosis factor.