Cure and vaccination – more steps forward in understanding persistence of HIV and how we might deal with it

Editor’s notes: CD32a is the exciting new marker for T-lymphocytes that seem to harbour the reservoir for HIV in peripheral blood.  These cells form a very small proportion of all CD4 T-lymphocytes, but they host copies of the virus in their DNA that can be woken up and start replicating again.  While this is still a discovery at the level of basic immunology, it raises important possibilities for measuring the reservoir and perhaps for intervening directly to drain it.  It may also lead on to further basic biological understanding of why this particular transmembrane protein should be so significantly expressed in latently infected cells but not in bystanders [Descours B et al., Richman DD].

Two papers are relevant to the push for an HIV vaccine.  A new mathematical model by Medlock J et al. highlights the potential contribution of a vaccine (or indeed other prevention technologies) over and above the impact of better diagnosis, linkage and treatment of people living with HIV as framed in the 90:90:90 treatment target of UNAIDS.  Of course, a significant advantage of a vaccine or a prevention technology is that primary prevention leads to a more rapid reduction in the number of people living with HIV and the associated costs of lifelong ART. UNAIDS strategy already includes a major push for those prevention tools that have been shown to work, with emphasis on combination prevention including structural (such as incentives to keep girls in school and improving access to condoms), behavioural (such as increasing condom usage) and biomedical (such as PrEP) elements within an approach that prioritizes the highest burdened locations and populations.  It is not clear that this new model has incorporated these wider prevention programmes in their baseline scenarios. Nonetheless the conclusion is still that we should maintain our enthusiasm for the ongoing and imminent large scale clinical trials of vaccine candidates!

And finally for this month, another encouraging immunotherapy study from NIAID.  In a macaque model using a humanized SHIV (a virus that still infects macaques but has been engineered to express HIV proteins), Nishimura Y et al. found a big difference when treatment was stopped between standard ART and infusions of broadly neutralizing antibodies infused around the time of infection.  Whereas the viral load rebounded soon after the ART was stopped, several of the macaques were able to continue to suppress the SHIV for up to two years after the infusion of antibodies.  The mechanism was shown to be through the CD8 T cell pathway, since removal of these cells led to rapid viral rebound in the antibody treated animals. With each new discovery in the animal and immunology laboratories, we get a little closer to understanding what it might take to develop an effective vaccine that could provide durable protection against HIV or provide effective treatment or therapeutic enhancement that allowed people living with HIV to no longer require ART.  That is a goal that we are all pushing towards!

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses.

Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, Reynes J, Lacabaratz C, Levy Y, Schwartz O, Lelievre JD, Benkirane M. Nature. 2017 Mar 23;543(7646):564-567. doi: 10.1038/nature21710.Epub 2017 Mar15.

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

Abstract access [1] 

HIV: Finding latent needles in a haystack.

Richman DD. Nature. 2017 Mar 23;543(7646):499-500. doi: 10.1038/nature21899. Epub 2017 Mar15.

Antiretroviral therapy can keep HIV at bay, but a few cells remain infected, so the disease cannot be cured. The discovery of a protein that marks out these infected cells will facilitate crucial studies of this latent viral reservoir. 

Abstract access [2] 

Effectiveness of UNAIDS targets and HIV vaccination across 127 countries.

Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Proc Natl Acad Sci U S A. 2017 Mar 20. pii: 201620788. doi:10.1073/pnas.1620788114. [Epub ahead of print]

The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035. Achieving the Joint United Nations Program on HIV/AIDS 95-95-95 target was estimated to avert 25 million [20M, 33M] of these new infections, and an additional 6.3 million [4.8M, 8.7M] reduction was projected with the 2020 introduction of a 50%-efficacy vaccine gradually scaled up to 70% coverage. This added benefit of prevention through vaccination motivates imminent and ongoing clinical trials of viable candidates to realize the goal of HIV control.

Abstract access [3] 

Early antibody therapy can induce long-lasting immunity to SHIV.

Nishimura Y, Gautam R, Chun TW, Sadjadpour R, Foulds KE, Shingai M, Klein F, Gazumyan A, Golijanin J, Donaldson M, Donau OK, Plishka RJ, Buckler-White A, Seaman MS, Lifson JD, Koup RA, Fauci AS, Nussenzweig MC, Martin MA. Nature. 2017 Mar 23;543(7646):559-563. doi: 10.1038/nature21435. Epub 2017 Mar13.

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

Abstract access [4] 

  • [8]