Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

Halper-Stromberg, Ariel; Nussenzweig, Michel C.

doi:10.1172/jci80561

Cited by 64 publications

(76 citation statements)

References 93 publications

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“…In particular, Q 2 VOA may be a sensitive assay with which to measure changes in the reservoir that result from immune-targeted interventions (39)(40)(41)(42). Viruses isolated from the replication-competent latent reservoir demonstrated a broad range of neutralization sensitivity to bNAbs, and may also show differing levels of sensitivity to immune-based interventions.…”

Section: Discussionmentioning

confidence: 99%

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

Lorenzi

Cohen

Cohn

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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164

219

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HIV-1–infected individuals harbor a latent reservoir of infected CD4+ T cells that is not eradicated by antiretroviral therapy (ART). This reservoir presents the greatest barrier to an HIV-1 cure and has remained difficult to characterize, in part, because the vast majority of integrated sequences are defective and incapable of reactivation. To characterize the replication-competent reservoir, we have combined two techniques, quantitative viral outgrowth and qualitative sequence analysis of clonal outgrowth viruses. Leukapheresis samples from four fully ART-suppressed, chronically infected individuals were assayed at two time points separated by a 4- to 6-mo interval. Overall, 54% of the viruses emerging from the latent reservoir showed gp160 env sequences that were identical to at least one other virus. Moreover, 43% of the env sequences from viruses emerging from the reservoir were part of identical groups at the two time points. Groups of identical expanded sequences made up 54% of proviral DNA, and, as might be expected, the sequences of replication-competent viruses in the active reservoir showed limited overlap with integrated proviral DNA, most of which is known to represent defective viruses. Finally, there was an inverse correlation between proviral DNA clone size and the probability of reactivation, suggesting that replication-competent viruses are less likely to be found among highly expanded provirus-containing cell clones.

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Section: Discussionmentioning

confidence: 99%

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

Lorenzi

Cohen

Cohn

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

164

219

View full text Add to dashboard Cite

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“…In reality, MAbs likely exert anti-HIV effects in multiple ways, including by prevention of cellular infection; targeting of infected cells, including FcR-positive cells or complement, for destruction by Fc-mediated effects (6)(7)(8)(9); or delivery of a toxic payload to cells in the form of immunoconjugates (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). It is often assumed that the same MAbs that prevent the transmission of infection are also the most effective in eliminating persistently infected cells (21,22), despite evidence to the contrary (6,13,16,19). Now that a new generation of broadly neutralizing MAbs (bnMAbs) has been developed (1-4, 8, 9, 23-27), it is important to revisit this issue.…”

Section: Importancementioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fcmediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIVinfected cells and eradicate persistent reservoirs of HIV infection.IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.

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“…The kick-and-kill paradigm gained traction when it was demonstrated that latency reversal (kick) alone, with the LRA vorinostat, was insufficient to cause the death of infected cells in a postactivation in vitro latency model, whereas the addition of expanded HIV-specific CD8 + T cells resulted in infected cell elimination (5). Others have since reported similar results using additional in vitro latency models, combined with natural or engineered CD8 + T cells, or NK cells as effectors (9)(10)(11)(12)(13)(14). These results have motivated the translation of the kick-and-kill approach into clinical trials that, thus far, have failed to achieve reductions in infectious viral reservoirs (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

Huang

Ren

Thomas

et al. 2018

Journal of Clinical Investigation

160

151

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Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

Cited by 64 publications

References 93 publications

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

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