HIV transmission and biomedical prevention

Recent failures and successes of biomedical prevention in conjunction with studies of HIV discordant couples (ie. where one partner is HIV positive and the other HIV negative and thus at risk of acquisition of HIV infection), has led to seminal contributions which give us a greater understanding of how HIV is spread from person to person.

Biomedical prevention in the form of topical microbicides (essentially lubricants that can kill or inhibit HIV) over the past decade has evolved from using formulations that essentially consisted of spermicidal detergents through to gel formulations that contain the same or similar ingredients to current antiretroviral drugs (reviewed in [124]. Whilst the first clinical trials using the spermicidal detergent Noxanol-9 (N-9) actually increased the incidence of HIV transmission [125] and following trials using polyanion based gels either enhanced or had limited effect [79, 126], they did provide important evidence with regards to how the virus was spread. For instance, the use of N-9 and its deleterious effects on the genital mucosa, illustrated how primary mucosal barriers were essential for blocking the incoming virions. The combined knowledge of the early microbicide trials (including polyanions) further demonstrated that the maintenance of good reproductive health further strengthened these primary barriers and thus limited the numbers of people contracting HIV infection through sex. The more recent studies initially using microbicides with antiretrovirals [127], combined with studies on pre-exposure antiretroviral treatment for recipients and treatment as prevention in HIV positive donors [128] also emphasized that there is a clear window during HIV transmission that can be targeted at the recipient and donor level [128]. One of the most successful trials in this latter context was HPTN 052. In this trial of HIV serodiscordant couples,  treatment of the infected partner led to a reduction in HIV transmission events of 96% [128]. Thus, successful control of HIV viral load in the donor, as is the case with limiting mother-to-child HIV transmission [129], is paramount in limiting the spread between people.

Whilst the prevention strategies discussed above gave broad insights into HIV transmission and how to prevent it, the studies of early HIV acquisition in HIV discordant couples gave at high resolution, the viral genetic footprint that is needed for a virus to cross hosts. The study of the genetic make-up of HIV strains that are the first detected during infection pointed to an extreme bottleneck where only the fittest virus is transmitted [130]. Curiously, the genetic diversity of transmitting strains is reflected in the ease with which the virus can infect. For instance, there is greater genetic diversity in HIV founder strains that are transmitted from male to female compared to female to male transmitting viruses. In addition those recipients with additional risk factors, such as sexually transmissible infections (STIs), further relaxes the genetic bottleneck of the virus and allows a more diverse viral population to pass rather than a stringently defined transmitting strain [130, 131]. Whilst the genetic make-up of the incoming virions in the early stages of HIV transmission is now mapped in large cohorts at fine detail with near whole HIV genomes, understanding the actual biological phenotype of the transmitting strain is still under consideration [130, 132-139]. Recent studies by Carlson and colleagues point to the transmitting strain being the “fittest” virus [130]. That is, the virus that makes it across the mucosa and has the ability to sustain early and robust viral replication prior to the mounting of an immune response. Whilst most researchers point to changes in HIV envelope, it is rather the overall genetic makeup of the virus that dictates the fitness of virus in vivo. As to whether the HIV envelope in a transmitting strain has a preference for HIV targets, in in vitro assays there is support for founder viruses to rely on high levels of CD4 and thus having a preference for CD4+ T cells [132, 137, 140]. That said, the appearance of HIV within the brain is largely mediated through macrophage infections and thus the clear-cut distinction that transmitting strains preferentially infect CD4+ T cells rather than other known HIV targets like dendritic cells and macrophages, is still a topic of debate. Even if founder strains did preferentially target CD4+ T cells, we must note that other HIV reservoirs, like those in macrophages, do exist in vivo and must be taken into context for the overall pathogenesis in vivo (whether that be during the acute or chronic stages of disease).