HIV immune evasion and vaccines

Introduction

Human immunodeficiency virus 1 (HIV-1) predominantly infects activated CD4+ T-cells, which are central drivers of adaptive immune responses. As such, HIV-1 depletes these CD4+ T-cells over time. Initial infection occurs at mucosal sites, such as the gut or genital tracts, where nearby CD4+ T-cells become quickly depleted. Untreated patients, unsurprisingly, become immunocompromised and thus susceptible to a myriad of opportunistic infections (Figure 1), of which perhaps the most notable is Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV is an otherwise benign virus in immunocompetent individuals; however, in immunocompromised people, it can cause blood cancers.

Importantly, early HIV-1 infection can also cause TH17 cell depletion, cells which are key in maintaining the gut barrier (a site of constant mechanical shearing) through the release of regulatory molecules called cytokines. This leads to perforations, which gut bacteria can use to enter the circulation and cause systemic inflammation.

More than 40 years after HIV-1’s first isolation, there is yet to be an approved vaccine, a stark contrast to the incredibly rapid success surrounding vaccine efforts against SARS-CoV-2. Though antiretrovirals have been largely successful in controlling the disease, mitochondrial toxicities have persisted throughout every era of HIV-1 treatment. Recent advances in long-acting injectables demonstrate remarkable efficacy and safety, being effective at the picomolar range and displaying toxicity only when used at >1,000,000x the half-maximum effective concentration. However, such approaches have yet to be adopted globally. There is also the problem of patient adherence/ regular dosing. Indeed, vaccine development for HIV-1 remains a top priority, as per the World Health Organisation.

The molecular immunology of HIV

Vaccines work by raising humoral (antibody) responses to essential regions of viruses, typically those which the virus needs in order to enter cells. Antibodies which block viral entry prevent infection, and these neutralising antibodies are the benchmark of vaccine efficacy. HIV-1 uses its Env protein to enter, which is made up of the gp41 and gp120 proteins (Figure 2). Antibodies against HIV-1 Env can block receptor binding and fusion with target cells, thereby preventing the virus from entering and completing its replicative cycle.

However, the gp120 portion of the Env protein has the ability to fall off, causing the host’s immune system to generate non-neutralising antibodies against regions of the free gp120 which used to be hidden when gp120 was still a part of the Env protein. Furthermore, strong humoral responses are also generated against the non-functional gp41 stumps left behind after gp120 shedding. These methods of decoying work together to help the virions evade neutralisation. Furthermore, HIV-1 has the remarkable ability to cover gp120 in cellular glycans (sugars). As a result, it is unlikely to be recognised by the immune system (Figure 3). In fact, ~50% of gp120’s molecular mass is constituted by these glycans derived from the host cell. Such masking means that on top of the decoying methods mentioned above, even the functional entry components themselves have very few sites against which neutralising antibodies can be raised.

Even in the rare event that the host generates neutralising antibodies against Env, the virus has yet another ace up its sleeve. Being a retrovirus, part of HIV-1’s life cycle involves reverse transcription of its viral RNA genome into complementary DNA, which can be integrated into the host genome (Figure 4). This is mediated by the reverse transcriptase enzyme, which is particularly error-prone, giving HIV-1 a high mutational rate, and thus a far greater likelihood of evolving favourable qualities. These include mutations which would change the protein enough to make sure that neutralising antibodies can no longer bind. 

Conclusion

HIV-1 is a case study in viral immune evasion from humoral responses, with such strategies underpinning the past 40+ years of failure to produce a viable, widely adopted vaccine. Going forward, advances in treatment of HIV-1 may benefit from looking at unique instances of individuals with favourable mutations which provide protection against HIV-1. One such group of individuals are “elite controllers”, who possess mutations in their CCR5 receptor, one of the co-receptors on CD4 T-cells which HIV-1 uses to enter and cause disease. These individuals maintain low levels of HIV-1 in their blood and normal T-cell counts, despite no intervention. Indeed, these instances of tolerating an otherwise deadly virus make gene editing technologies an attractive avenue to pursue for treatment of HIV-1 infected individuals. Such approaches are subject to controversy however, due to the ethical issues surrounding gene editing in humans. In fact, in 2018, He Jiankui, a researcher in the field, illegally created the world’s first “designer babies”, with modified CCR5 genes. He was subsequently sent to prison and fined the equivalent of £327,360.

Written by Yusuf Ibrahim

Related articles: Treatments for HIV- CRISPR-Cas9, antiretroviral therapy

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