Exploring the Maintenance of HIV in Controllers and Non-controllers

Even in a rare group of people with natural HIV-specific immune responses that allow for viral control without the use of antiretroviral therapy (ART; HIV controllers), a reservoir of HIV-infected CD4 T cells is maintained in the lymph nodes, both inside and outside the follicle, according to the results of a study published recently in Cell.¹

The study was presented by first author Eli A. Boritz, MD, PhD, from the Human Immunology Section, Vaccine Research Center of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, and his colleagues. The motivation for the study came from the results of recent studies that have identified clonal expansion of HIV-infected CD4 T cells despite treatment with ART.^2-5 The elucidation of the mechanisms underlying this persistence has therefore taken on a new sense of urgency.

To further investigate the mechanisms of HIV persistence during natural virologic control, as well as examine cellular processes underlying the maintenance of HIV in controllers and in non-controllers, Dr. Boritz and his colleagues conducted a variety of experiments using CD4 T cell subsets extracted from the blood of 14 patients with plasma HIV RNA levels <1,000 copies/mL during chronic infection without the use of ART (controllers) and six patients with plasma HIV RNA levels >10,000 copies/mL not on ART (non-controllers). The CD4 T cell subsets from these two populations were studied to explore differences regarding the distribution of HIV, as well as their HIV DNA sequences, clonality, and inducible proviruses. Additionally, HIV from the lymphoid tissue of four controllers was assessed in order to elucidate the origin of circulating CD4 T cells with unique induced viruses.

When asked about his thoughts on the study as a whole, senior author Dr. Boritz told Contagion, "Our goal was to elucidate the origins of virus persistence in HIV controllers, as the mechanisms underlying this have remained stubbornly unclear. We specifically identified multiple distinct cellular processes by which HIV persists in controllers. We sequenced vast numbers of viruses to map these processes within different anatomic and functional compartments of the immune system (in peripheral blood and lymph nodes). We found three processes that maintain the reservoir: (1) Expansion of T cells in blood containing mostly non-viable virus; (2) An active reservoir of ongoing replication in lymph node predominantly but NOT exclusively in follicles; and (3) a tiny population of critically important cells circulating in blood that can be induced to produce viruses related to the active pool in lymph nodes. This last population of cells is important as it likely disseminates productive virus around the body."

Regarding the broader implications of his team's study results, Dr. Boritz told Contagion, "... we have identified the parts of the HIV reservoir that should be the focus of cure approaches; we provide a uniquely broad and deep view of the HIV-infected CD4 T cell pool in vivo and show that the barrier to HIV cure in the setting of natural virologic control may be greater than previously thought." Boritz et al also noted that any future approaches to a functional or sterilizing cure for HIV would need to address all three of the distinct cellular processes identified in the study in order to have any potential for success.

Listed below are helpful key takeaway points provided by Dr. Boritz and colleagues regarding their study.

• In HIV controllers, both T follicular helper (T_FH) and non-T_FH lymph node CD4 T cells contain HIV
• Lymph node viruses in both T_FH and non-T_FH have attributes of active replication
• Rare, recently infected cells that produce virus upon stimulation circulate in blood
• Archival proviruses predominant in clonally expanded blood cells can be inducible

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.

References

1. Boritz EA, Darko S, Swaszek L, et al. Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell. 2016;166:1—12.
2. Cohn LB, Silva IT, Oliveira TY, et al. HIV-1 integration landscape during latent and active infection. Cell. 2015;160:420—432.
3. Maldarelli F, Wu X, Su L, et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345:179—183.
4. Simonetti FR, Sobolewski MD, Fyne E, et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci USA. 2016;113:1883—1888.
5. Wagner TA, McLaughlin S, Garg K, et al. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science. 2014;345:570—573.