Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

Abstract

Once a death sentence, HIV is now considered a manageable chronic disease due to the development of antiretroviral therapy (ART) regimens with minimal toxicity and a high barrier for genetic resistance. While highly effective in arresting AIDS progression and rendering the virus untransmissible in people living with HIV (PLWH) with undetectable viremia (U=U) [1, 2]), ART alone is incapable of eradicating the "reservoir" of resting, latently infected CD4⁺ T cells from which virus recrudesces upon treatment cessation. As of 2022 estimates, there are 39 million PLWH, of whom 86% are aware of their status and 76% are receiving ART [3]. As of 2017, ART-treated PLWH exhibit near normalized life expectancies without adjustment for socioeconomic differences [4]. Furthermore, there is a global deceleration in the rate of new infections [3] driven by expanded access to pre-exposure prophylaxis (PrEP), HIV testing in vulnerable populations, and by ART treatment [5]. Therefore, despite outstanding issues pertaining to cost and access in developing countries, there is strong enthusiasm that aggressive testing, treatment, and effective viral suppression may be able to halt the ongoing HIV epidemic (ie, UNAIDS' 95-95-95 targets) [6-8]; especially as evidenced by recent encouraging observations in Sydney [9]. Despite these promising efforts to limit further viral transmission, for PLWH, a "cure" remains elusive; whether it be to completely eradicate the viral reservoir (ie, cure) or to induce long-term viral remission in the absence of ART (ie, control; Figure 1). In a previous salon hosted by Pathogens and Immunity in 2016 [10], some researchers were optimistic that a cure was a feasible, scalable goal, albeit with no clear consensus on the best route. So, how are these cure strategies panning out? In this commentary, 8 years later, we will provide a brief overview on recent advances and failures towards identifying determinants of viral persistence and developing a scalable cure for HIV. Based on these observations, and as in the earlier salon, we have asked several prominent HIV cure researchers for their perspectives.

Keywords: ART; HIV; HIV control; HIV cure; SIV; persistence; reservoir.

Figure 1.

Conceptualization of longitudinal HIV-1 plasma RNA (at left; red line) and tissue DNA content (at right; blue line) during long-term antiretroviral therapy (ART; orange background) and following ART analytical therapy interruption (ATI; white background) for pathogenic disease progression (top; grey) and therapies conferring viral control (middle; green), including potentially with latency reversal (dashed line), or cure (bottom; purple).

Figure 2.

(1) CCR5⁺ CD4⁺ T cells are efficiently infected with HIV-1 resulting in the establishment of a pool of productively infected cells. (2) These highly activated effector CD4⁺ T cells support robust levels of viral replication facilitating the rapid escape from cytolytic T lymphocyte (CTL) responses and inducing a state of CTL exhaustion due to chronic antigenic stimulation. (3) Viral replication leads to the rapid, exponential infection of bystander CD4⁺ T cells and systemic viremia that progressively contributes to CD4⁺ T cell depletion and AIDS progression. Alternatively, antiretroviral therapy (ART) is highly effective in blocking de novo infection of vulnerable cells, thereby indirectly reducing plasma viremia as productively infected cells turn over due to viral cytopathic effects and/or immune-mediated clearance. (4) A subset of productively infected effector CD4⁺ T cell reverts to long-lived, resting, memory cells in which viral latency is established. (5) During long-term ART, latently infected memory CD4⁺ T cells persist indefinitely. This persistence has been linked to clonal expansion via homeostatic proliferation, inhibition of apoptotic pathways (ie, prosurvival), and impaired immunosurveillance. (6) Some immunotherapy cure strategies seek to transiently reverse viral latency to enhance viral peptide presentation and the expression of viral envelope on the cell surface (ie, “shock”), thus rendering latently infected cells susceptible to elimination by HIV-specific CD8⁺ T cells or by natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC; ie, “kill”), respectively. (7) To promote the immune-mediated clearance of reactivated cells, in an environment where ART protects uninfected cells from infection, combination therapies may be applied to augment the cytotoxicity, activation, homing, and/or differentiation of responding CD8⁺ T cells and NK cells.

Figure 3.

Schematic of the workflow for hematopoietic stem cell transplantation (HSCT) to an ART-suppressed PLWH with wild-type CCR5 (yellow background). Allogeneic HSCT (alloHSCT; red background) is performed using mobilized CD34⁺ HSCs isolated from the blood of an uninfected CCR5^Δ32/Δ32 donor (blue background) and administered to the patient following conditioning with chemotherapy, radiotherapy, immunosuppressants, and/or immunomodulators to promote cell engraftment and to prevent graft rejection. The alloHSCT conditioning regimen induces systemic tissue damage and a breakdown of the gut epithelium resulting in the production of pro-inflammatory cytokines (IL-1, IL-6, and TNFα) and the influx of bacterial elements, such as lipopolysaccharides (LPS), causing robust dendritic cell and macrophage activation. Autologous transplantation (green background) is performed using CD4⁺ T cells isolated from the blood of the ART-suppressed PLWH. Cells for autologous transplantation then undergo ex vivo gene editing to knock out CCR5 and are then re-infused to the donor. Eradication of the HIV reservoir (grey background) occurs upon complete chimerism with donor cells. Infected CD4⁺ T cells are subject to clearance by activated donor cytotoxic T cells against minor recipient antigens as a graft-versus-host disease (GvHD) response. Upon ART interruption, engrafted donor CCR5^Δ32/Δ32 CD4⁺ T cells are refractory to infection if virus is produced by a residual reservoir.