Toward T Cell-Mediated Control or Elimination of HIV Reservoirs: Lessons From Cancer Immunology

Abstract

As the AIDS epidemic unfolded, the appearance of opportunistic infections in at-risk persons provided clues to the underlying problem: a dramatic defect in cell-mediated immunity associated with infection and depletion of CD4+ T lymphocytes. Moreover, the emergence of HIV-associated malignancies in these same individuals was a clear indication of the significant role effective cellular immunity plays in combating cancers. As research in the HIV field progressed, advances included the first demonstration of the role of PD-1 in human T cell exhaustion, and the development of gene-modified T cell therapies, including chimeric antigen receptor (CAR) T cells. In the intervening years, the oncology field has capitalized on these advances, effectively mobilizing the cellular immune response to achieve immune-mediated remission or cure of previously intractable cancers. Although similar therapeutic advances have not yet been achieved in the HIV field, spontaneous CD8+ T cell mediated remission or functional cure of HIV infection does occur in very small subset of individuals in the absence of anti-retroviral therapy (ART). This has many similarities to the CD8+ T cell mediated functional control or elimination of cancers, and indicates that immunotherapy for HIV is a rational goal. In HIV infection, one major barrier to successful immunotherapy is the small, persistent population of infected CD4+ T cells, the viral reservoir, which evades pharmacological and immune-mediated clearance, and is largely maintained in secondary lymphoid tissues at sites where CD8+ T cells have limited access and/or function. The reservoir-enriched lymphoid microenvironment bears a striking resemblance to the tumor microenvironment of many solid tumors–namely high levels of anti-inflammatory cytokines, expression of co-inhibitory receptors, and physical exclusion of immune effector cells. Here, we review the parallels between CD8+ T cell-mediated immune control of HIV and cancer, and how advances in cancer immunotherapy may provide insights to direct the development of effective HIV cure strategies. Specifically, understanding the impact of the tissue microenvironment on T cell function and development of CAR T cells and therapeutic vaccines deserve robust attention on the path toward a CD8+ T cell mediated cure of HIV infection.

TCF-1 regulates the stem-like memory potential of HIV-specific CD8+ T cells in elite controllers

“…Within the population of multimer+ HIV-specific CD8+ T cells, we found that TCF-1 expression was associated with patterns of phenotypic marker expression typically found in central memory CD8+ T cells, with a positive correlation between TCF-1 and CD127 expression (Spearman correlation, r=0.64, p<0.0001), and a negative correlation between TCF-1 and 10 Granzyme B (r=-0.64, p<0.001), and T-bet expression (r=-0.53, p<0.001), both across the whole cohort and specifically within HIV-specific CD8+ T cells isolated from controllers ( Fig. 2D).…”

“…The goal of many immune-based strategies that aim to enhance the control of HIV is to elicit functional, non-exhausted, and durable HIV-specific CD8+ T cells that have the stem-like memory T cell capacity to rapidly expand into secondary effector cells that can kill HIV-infected cells (10,12). We hypothesized that TCF-1, a Wnt signaling transcription factor known to regulate T cell "stemness" in several other contexts, might also regulate the expansion capacity of HIVspecific CD8+ T cells.…”

“…Therefore, even though they can initially control the viral load (5)(6)(7)(8)(9), HIV-specific CD8+ T cells that persist during the chronic phase of infection fail to eradicate infected cells from the body. Generating long-lived, non-exhausted antigen-specific CD8+ T cells that have stem-like T cell memory properties (i.e., the capacity to proliferate and to generate a burst of cytotoxic effector cells upon encountering cognate antigen) is the focus of several immunotherapeutic strategies (e.g., therapeutic vaccination, blockade of co-inhibitory receptors such as PD-1, and adoptive T cell therapies) for HIV (10)(11)(12) and other diseases in which CD8+ T cell exhaustion is observed, such as other chronic infections and cancers (13).…”

Broadly active zinc finger protein-guided transcriptional activation of HIV

“…Alternatively, ZFP-362 could be used to induce sustained expression of HIV to allow for or enhance chimeric antigen T cell (CAR) targeting of infected cells. Notably, the lack of HIV antigen has proven problematic for developing robust anti-HIV CARs [41,42]. However, for either of these approaches to prove viable, the issue of delivery remains to be solved.…”

Lung Cancer (LC) in HIV Positive Patients: Pathogenic Features and Implications for Treatment

“…Chronic viral infection and cancer are pathological conditions dominated by chronic inflammation and an insufficient antigen clearance. The consequence is a difficult construction in HIV patients of a functional anti-cancer immune response, with T cells becoming exhausted for a high acquired expression of different negative check-point receptors [71] (Figure 2).…”