Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations

Abstract

Despite antiretroviral therapy (ART), HIV-1 persists in a stable latent reservoir1, 2, primarily in resting memory CD4+ T cells3, 4. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed5 and tested both in vitro and in vivo6–8. A key remaining question is whether virus-specific immune mechanisms including cytolytic T lymphocytes (CTL) can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…[7][8][9][10][11] Because residual HIV expression continues despite effective ART [12][13][14][15][16] and is required for viral rebound, HIV-infected cells should theoretically be targetable by a T cell therapeutic agent. Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance. 24,25 Over the last decade, major advances have been made in engineering human T cells via introduction of chimeric antigen receptors (CARs) to enable specific lysis of pathogenic targets.…”

Multifarious immunotherapeutic approaches to cure HIV-1 infection

“…12 Early treatment also prevents the latent viral reservoir from becoming dominated by HIV-1 variants that have mutated to escape cytotoxic T lymphocytes (CTL); this has implications for both therapeutic vaccine design and HIV cure strategies. 13 Furthermore, earlier initiation of cART and higher nadir CD4 T-cell counts have been associated with the preservation of functional recall T-cell responses.…”

“…However, immunization in conjunction with cART may lead to a reversal of anergy by selective induction and activation of specific memory T-cell responses against a number of viral proteins. 3,20 By presenting viral proteins in novel ways, with or without specific adjuvants, or by presenting both immunodominant and subdominant epitopes, specific beneficial memory responses may be induced or augmented, 13 and T-cell anergy reversed. That said, even administered in the context of cART, therapeutic immunization is likely to have little efficacy if used without other concomitant immunotherapies due to the immunocompromised status of chronically HIV-1-infected patients.…”

“…57 The vast majority of viruses in the latent reservoir of patients treated during chronic HIV-1 infection comprise CTL escape mutations, which are rare in the reservoirs of subjects treated during acute infection. 13 Recent work shows that only 12% of proviruses are non-mutated and replication competent. 58 However, measurement of HIV-1 latency reversal ex vivo using a different approach revealed that only 1.5% of proviruses in resting CD4 T cells were able to produce virions following CD3/ CD28 activation.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…It has been suggested that variable sequences can serve as immunodominant “decoys” that can absorb immune reactivity, driving the emergence of escape mutations and potentially precluding responses against conserved protective epitopes. 29–35 The mechanisms of this preclusion, also referred to as immunodomination, 36 are varied. 37 , 38 Virus-specific T cells are responsible for controlling viremia in humans and macaques.…”