Immunological approaches to HIV cure.

Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization (FISH), we detect active HIV transcription in 14/18 people with HIV on suppressive ART, with a median of 28/million CD4+ T cells. While these cells predominantly exhibit abortive transcription, p24-expressing cells are evident in 39% of participants. Phenotypically diverse, active reservoirs are enriched in central memory T cells and CCR6- and activation-marker-expressing cells. The magnitude of the active reservoir positively correlates with total HIV-specific CD4+ and CD8+ T cell responses and with multiple HIV-specific T cell clusters identified by unsupervised analysis. These associations are particularly strong with p24-expressing active reservoir cells. Single-cell vDNA sequencing shows that active reservoirs are largely dominated by defective proviruses. Our data suggest that these reservoirs maintain HIV-specific CD4+ and CD8+ T responses during suppressive ART. 

Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells

Antiretroviral therapy (ART) regimens durably suppress HIV replication, but do not cure infection. This is partially attributable to the persistence of long-lived pools of resting CD4+ T-cells harboring latent replication-competent virus. Substantial clinical and pre-clinical research is currently being directed at purging this viral reservoir by combining pharmacological latency reversal with immune effectors, such as HIV-specific CD8+ T-cells, capable of eliminating reactivated targets – the so called ‘shock-and-kill’ approach. However, several studies indicate the latency reversing agents may affect CD8+ T-cell function. The current review aims to frame recent advances, and ongoing challenges, in implementing ‘shock-and-kill’ strategies from the perspective of effectively harnessing CD8+ T-cells. We review and contextualize findings indicating that latency reversing agents often have unintended impacts on CD8+ T-cell function, both detrimental and beneficial. We identify and attempt to bridge the gap between viral reactivation, as measured by the detection of RNA or protein, and bona fide presentation of viral antigens to CD8+ T-cells. Finally, we highlight factors on the effector (CD8+) and target (CD4+) cell sides that contribute to whether or not infected cell recognition results in killing/elimination. These perspectives may contribute to an integrated view of ‘shock-and-kill’, with implications for therapeutic development.

/pdf/diverse-impacts-of-hiv-latency-reversing-agents-on-cd8-t-5eyzxt0rft.pdf

Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure.

Primary cell models of human immunodeficiency virus (HIV) latency have become tools to both understand the mechanisms involved in establishment of latency and test preclinical strategies toward HIV-1 cure. These models rely on infection of CD4 T cells from healthy donors. As such, these models provide an opportunity to explore the role of biological sex, age, and HIV status on establishment and reactivation of latent HIV in vitro. We have used an established primary cell model of latency based on the generation of latently infected central memory CD4 T cells with the CXCR4 strain HIV-1NL4-3 to address whether these variables influence (i) HIV-1NL4-3 replication, (ii) establishment of latency, and (iii) latency reversal in CD4 T cells. Our results indicate that replication of HIV-1NL4-3, but not establishment of latency, is influenced by the age of female, but not male, donors. Moreover, the frequency of latently infected cells in this model is directly correlated with levels of productive infection in both male and female donors independent of age. We did not find differences in the ability of five different latency-reversing agents to reactivate latent HIV-1NL4-3. Finally, we have found that this model can be generated using cells from aviremic participants. In conclusion, we have further characterized the central memory T cell model of latency regarding biological sex and age and demonstrated that this model is suitable for use with cells isolated from aviremic participants, opening the opportunity to use this primary cell model to address cure approaches, including shock and kill, in HIV-infected individuals.

/pdf/influence-of-biological-sex-age-and-hiv-status-in-an-in-3z1clvt7xb.pdf

Influence of Biological Sex, Age, and HIV Status in an In Vitro Primary Cell Model of HIV Latency Using a CXCR4 Tropic Virus.

Abstract Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4 + T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8 + T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence. 

Viral and host mediators of non-suppressible HIV-1 viremia.

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

/pdf/t-cell-responses-targeting-hiv-nef-uniquely-correlate-with-2nc1b2x6lw.pdf

T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

21 Patient-derived HIV reservoirs can be stably engrafted into NSG mice and reactivated by latency-reversing agents in vivo

Susceptibility to neutralization by bnAbs orrelates with infected cell binding for a panel of clade B HIV reactivated from latent reservoirs

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T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

21 Patient-derived HIV reservoirs can be stably engrafted into NSG mice and reactivated by latency-reversing agents in vivo

Susceptibility to neutralization by bnAbs orrelates with infected cell binding for a panel of clade B HIV reactivated from latent reservoirs