Human Immunodeficiency Virus (HIV) is a retrovirus that primarily infects CD4+ T cells, a population of immune cells that participate in host defense. HIV depletion of CD4+ T cells can lead to acquired immune deficiency syndrome (AIDS) unless identified and met with lifelong treatment with antiretroviral therapy (ART), which is administered as a combination of antiretroviral pharmaceuticals targeting various stages of the HIV replicative life cycle. The principle goals of ART are to (a) achieve and maintain suppression of viremia below current levels of detection, (b) improve overall immune function through increased CD4+ T cell counts, and (c) increase the duration and quality of life of HIV-positive individuals1. Importantly, ART does not eradicate the virus, as HIV can reside in viral reservoirs in latently infected CD4+ cells. Since rapid viral rebound and concurrent CD4+ T cell decline follow ART cessation, successful suppression of the HIV viral load requires strict adherence to individually prescribed regimen.
The availability of ART has increased the life expectancy of HIV-positive individuals, with some cohorts nearing the lifespan average of the general population. Yet, sexual transmission of the virus continues to contribute significantly to global HIV incidence and demonstrates the need for effective and accessible HIV prevention. Obstacles in various HIV prevention regimen are comprised of biological and social factors, and both must be addressed to extend aid to all persons at risk for HIV.
One prominent prevention regimen involves the aforementioned administration of ART in HIV-positive individuals, otherwise known as treatment as prevention (TasP). Introduction of ART immediately after HIV diagnosis can reduce transmission of HIV in heterosexual serodiscordant partners by up to 96% compared to those that initiate ART upon low CD4+ cell counts at previously recommended thresholds (< 250 cells/mm2). These observations support the campaign of early ART introduction and demonstrate its potential role in improving sexual health. Results from the notable PARTNER study revealed that the risk of HIV transmission in both heterosexual and homosexual couples is effectively zero when HIV viral load is suppressed in the infected partner. Taken together, these results support the U=U (undetectable = untransmittable) campaign, which states that undetectable plasma levels of the HIV virus due to effective ART equate to a concentration too low for sexual transmission.
Similar to TasP, pre-exposure prophylaxis (PrEP) is a tool used in preventing HIV transmission through the pre-emptive administration of antiretrovirals. Unlike TasP, PrEP is given to HIV-negative individuals at high risk of infection and seeks to arrest its replication prior to viral dissemination upon exposure. Currently, there are more than 380,000 people who are taking PrEP worldwide, and it is a highly effective method for preventing HIV acquisition. The most common obstacle to PrEP efficacy is a lack of medical adherence, although there have been six cases of HIV infections despite high PrEP adherence to date. These cases arise when individuals are exposed to rare, drug-resistant strains of HIV.
Another HIV prevention regimen is post-exposure prophylaxis (PEP), which is aimed at preventing transmission in individuals after a potential HIV exposure. PEP prevents viral replication prior to dissemination, and often employs the same antiviral regimen as PrEP. PEP is most effective if initiated within 24 hours of suspected exposure, although it may be administered up to 72 hours post-infection. Neonatal antiviral prophylaxis treatment regimens have also been developed as a method of PEP treatment to reduce the likelihood of maternal-infant transmission.
Although these strategies contribute successfully to reducing HIV transmission at a population level, other biological and social determinants have been reported to influence their effectiveness in HIV prevention.
In the case of biological determinants of ART efficacy, the microbiome has been shown to affect how well drugs can penetrate various tissue sites. One noteworthy example is PrEP tissue-specific accumulation, which is slower in cervicovaginal tissue compared to the rectal mucosa, as its activity is influenced by vaginal microbial composition. The presence of Gardnerella vaginalis and other antiretroviral-metabolizing microbes have demonstrated to significantly decrease PrEP efficacy. There are also consequences regarding PrEP route of administration, which often vary by geographical location. In North America and Europe, most ART drugs are orally administered as a pill, while PrEP is often administered locally elsewhere. In South Africa, the commonly-used, locally-administered gels has medically yielded insignificant results in the presence of non-Lactobacillus dominant vaginal microbiota, while these differences were not observed if PrEP was orally administered. The efficacy of locally-administered PrEP, therefore, also depends on the biology and composition of vaginal microbiota.
“HIV prevention will require intricate solutions that intersect efficacious antiviral development and accessibility”
In addition to biological considerations, social factors also influence the efficacy of both TasP and PrEP. High adherence is essential to the efficacy of both ART strategies, and elements such as mental health, substance use, homelessness, and stigma must be addressed to reach all persons at risk for HIV. This is particularly important for young men who have sex with men (MSM) in serodiscordant relationships, as their medical adherence has been found to attenuate through time and may require adherence support to maintain low HIV transmission risk. Difficulties in addressing these structural barriers may have revealed consequences in British Columbia, Canada, where significantly higher incidences of HIV in young MSM (20-29 years) in Vancouver compared to their provincial average have emerged. Interview of self-identified gay, bisexual, and heterosexual men from Vancouver residents in the study identified heteronormative views of masculinity, stigma, and wait times as notable factors that deterred their HIV preventative action (e.g., regular HIV testing).
Aside from TasP, PrEP and PEP that are already in place, other exploratory means of HIV prevention as alternatives to long-term antiviral treatment include the use of CRISPR-Cas9-mediated genetic editing. Previous experiments have demonstrated inhibition of viral replication through successful knock-out of HIV regulatory genes in both latently and persistently HIV-1-infected T cells. Another study has revealed that combination ART-treated CD4+ T cells in humanized mice can be successfully targeted by the CRISPR-Cas9 system to remove integrated pro-viral DNA. This reveals the potential for CRISPR modification of latently-infected cells, which act as viral reservoirs that lie beyond the reach of current ART treatment.
The ethical and biological consequences of CRISPR in the context of human HIV prevention, however, have yet to be fully explored. The most notable example of this unmet need is exemplified by Dr. Jiankui He, who defied the ethics of the Southern University of Science and Technology in Shenzhen, China in his attempts to delete allele 32 of the HIV entry co-receptor ccr5 in twin baby girls. In addition to the unsuccessful generation of the CRISPR knock-out, the ccr5Δ32 mutation has also been linked to decreased protection against a variety of other infectious diseases. Understanding the full downstream consequences of human genetic modifications—including interference with off-target pathways—remains a matter of hindsight. Furthermore, HIV is highly mutative, and the virus may develop other methods for host cell invasion. This is exemplified in the co-opted use of CXCR4 as an additional co-receptor for HIV invasion, which has emerged in approximately 50% of HIV-positive individuals.
Although TasP and PrEP remain the most viable options for long-term HIV prevention, its accessibility remains an issue for marginalized cohorts. Addressing the stigma surrounding safe sex and HIV positivity will be necessary in encouraging early HIV testing and treatment, especially for younger individuals. A study performed by Golub et al. demonstrated that frank discussion of sexual history with young people of colour can lead to greater comprehension of PrEP use and its necessity in a follow-up survey. This demonstrates the need for structured outreach that extend beyond the clinic to encourage participation in STI preventative action. Thus, HIV prevention will require intricate solutions that intersect efficacious antiviral development and their accessibility. The barriers on the path towards large-scale HIV eradication, therefore, must be addressed from both scientific and social perspectives.
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