Human immunodeficiency virus type 1 (HIV-1) infection persists despite years of antiretroviral therapy (ART). To remove the stigma and burden of chronic infection, approaches to eradicate or cure HIV ...infection are desired. Attempts to augment ART with therapies that reverse viral latency, paired with immunotherapies to clear infection, have advanced into the clinic, but the field is still in its infancy. We review foundational studies and highlight new insights in HIV cure research. Together with advances in ART delivery and HIV prevention strategies, future therapies that clear HIV infection may relieve society of the affliction of the HIV pandemic.
Margolis and colleagues review progress and prospects toward developing a true cure for HIV-1 infection, focusing on the biological underpinnings of the “kick and kill” approach to curing HIV-1 infection, which couples reactivation of the latent, integrated provirus with immunotherapies to recognize and kill infected cells.
Antiretroviral therapy (ART) has transformed HIV from a fatal disease to a chronic condition. In recent years there has been considerable interest in strategies to enable HIV-infected individuals to ...cease ART without viral rebound, either by purging all cells infected harboring replication-competent virus (HIV eradication), or by boosting immune responses to allow durable suppression of virus without rebound (HIV remission). Both of these approaches may need to harness HIV-specific CD8
T cells to eliminate infected cells and/or prevent viral spread. In untreated infection, both HIV-specific and total CD8
T cells are dysfunctional. Here, we review our current understanding of both global and HIV-specific CD8
T cell immunity in HIV-infected individuals with durably suppressed viral load under ART, and its implications for HIV cure, eradication or remission. Overall, the literature indicates significant normalization of global T cell parameters, including CD4/8 ratio, activation status, and telomere length. Global characteristics of CD8
T cells from HIV
ART
individuals align more closely with those of HIV-seronegative individuals than of viremic HIV-infected individuals. However, markers of senescence remain elevated, leading to the hypothesis that immune aging is accelerated in HIV-infected individuals on ART. This phenomenon could have implications for attempts to prime
, or boost existing HIV-specific CD8
T cell responses. A major challenge for both HIV cure and remission strategies is to elicit HIV-specific CD8
T cell responses superior to that elicited by natural infection in terms of response kinetics, magnitude, breadth, viral suppressive capacity, and tissue localization. Addressing these issues will be critical to the success of HIV cure and remission attempts.
Human immunodeficiency virus (HIV) evolves within infected persons to escape being destroyed by the host immune system, thereby preventing effective immune control of infection. Here, we combine ...methods from evolutionary dynamics and statistical physics to simulate in vivo HIV sequence evolution, predicting the relative rate of escape and the location of escape mutations in response to T-cell-mediated immune pressure in a cohort of 17 persons with acute HIV infection. Predicted and clinically observed times to escape immune responses agree well, and we show that the mutational pathways to escape depend on the viral sequence background due to epistatic interactions. The ability to predict escape pathways and the duration over which control is maintained by specific immune responses open the door to rational design of immunotherapeutic strategies that might enable long-term control of HIV infection. Our approach enables intra-host evolution of a human pathogen to be predicted in a probabilistic framework.
Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4
T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore ...the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4
T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4
T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4
T cells from naïve cells, it is essential for the further transition of effectors to memory CD4
T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4
T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127
CD4
memory T cells increases, indicating restoration of effector to memory transition in CD4
T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4
T cells transition to long-lived, CD127
CD4
T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4
T cell memory formation will limit the generation of long-lived HIV-infected CD4
T cells and reduce the overall size of the stable HIV-1 reservoir.
Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR ...(Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.
CD8 T cells recognize infected and cancerous cells via their T-cell receptor (TCR), which binds peptide-MHC complexes on the target cell. The affinity of the interaction between the TCR and ...peptide-MHC contributes to the antigen sensitivity, or functional avidity, of the CD8 T cell. In response to peptide-MHC stimulation, the TCR-CD3 complex and CD8 co-receptor are downmodulated. We quantified CD3 and CD8 downmodulation following stimulation of human CD8 T cells with CMV, EBV, and HIV peptides spanning eight MHC restrictions, observing a strong correlation between the levels of CD3 and CD8 downmodulation and functional avidity, regardless of peptide viral origin. In TCR-transduced T cells targeting a tumor-associated antigen, changes in TCR-peptide affinity were sufficient to modify CD3 and CD8 downmodulation. Correlation analysis and generalized linear modeling indicated that CD3 downmodulation was the stronger correlate of avidity. CD3 downmodulation, simply measured using flow cytometry, can be used to identify high-avidity CD8 T cells in a clinical context.
Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell ...immunotherapeutic, on the HIV reservoir. HIV+, stably treated participants in whom resting CD4
T cell-associated HIV RNA (rca-RNA) increased after VOR exposure ex vivo and in vivo received 4 doses of AGS-004 every 3 weeks, followed by VOR every 72 hours for 30 days, and then the cycle repeated. Change in VOR-responsive host gene expression, HIV-specific T cell responses, low-level HIV viremia, rca-RNA, and the frequency of resting CD4
T-cell infection (RCI) was measured at baseline and after each cycle. No serious treatment-related adverse events were observed among five participants. As predicted, VOR-responsive host genes responded uniformly to VOR dosing. Following cycles of AGS-004 and VOR, rca-RNA decreased significantly in only two participants, with a significant decrease in SCA observed in one of these participants. However, unlike other cohorts dosed with AGS-004, no uniform increase in HIV-specific immune responses following vaccination was observed. Finally, no reproducible decline of RCI, defined as a decrease of >50%, was observed. AGS-004 and VOR were safe and well-tolerated, but no substantial impact on RCI was measured. In contrast to previous clinical data, AGS-004 did not induce HIV-specific immune responses greater than those measured at baseline. More efficacious antiviral immune interventions, perhaps paired with more effective latency reversal, must be developed to clear persistent HIV infection.
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