Depletion of CD4+ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques
Alexandra M. Ortiz, … , Cynthia A. Derdeyn, Guido Silvestri
Alexandra M. Ortiz, … , Cynthia A. Derdeyn, Guido Silvestri
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4433-4445. https://doi.org/10.1172/JCI46023.
View: Text | PDF
Research Article AIDS/HIV

Depletion of CD4+ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques

Abstract

CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte–depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell– and B cell–mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.

Authors

Alexandra M. Ortiz, Nichole R. Klatt, Bing Li, Yanjie Yi, Brian Tabb, Xing Pei Hao, Lawrence Sternberg, Benton Lawson, Paul M. Carnathan, Elizabeth M. Cramer, Jessica C. Engram, Dawn M. Little, Elena Ryzhova, Francisco Gonzalez-Scarano, Mirko Paiardini, Aftab A. Ansari, Sarah Ratcliffe, James G. Else, Jason M. Brenchley, Ronald G. Collman, Jacob D. Estes, Cynthia A. Derdeyn, Guido Silvestri

×

Figure 2

Anti-CD4 Ab induces major CD4+ T cell loss in blood, LN, and BM, followed by residual CD4+ T cell proliferation.

Options: View larger image (or click on image) Download as PowerPoint
Anti-CD4 Ab induces major CD4+ T cell loss in blood, LN, and BM, followe...
(A) Representative flow cytometry plots of percent circulating CD4+ T cells (relative to total CD3+ T cells) before and after Cdr-OKT4A-huIgG1 treatment. (B) Longitudinal assessment of percent and absolute number per μl of peripheral blood CD4+ T cells before and after Cdr-OKT4A-huIgG1 treatment. CD4+ T cell dynamics were significantly different between CD4+ lymphocyte–depleted RMs and controls from baseline to the time of infection (P < 0.001, linear mixed-effects model). (C) Longitudinal assessment of percent CD4+ T cells in the BM, LN, and RB. Percent CD3+CD4+ T cells was significantly lower in the BM (P = 0.0011) and LN (P = 0.0378) of CD4+ lymphocyte–depleted RMs (Student’s t test with Welch correction). Some baseline time points were unavailable in RB due to technical error (n = 4). (D) Longitudinal assessment of percent CD4+Ki67+ T cells in peripheral blood, significantly higher at the time of infection in CD4+ lymphocyte–depleted RMs (P = 0.0062, Student’s t test with Welch correction). (E) Correlation between peripheral CD4+ T cell absolute count (orange) and percent CD4+Ki67+ T cells (green) in CD4+ lymphocyte–depleted animals (P < 0.0001, R2 = 0.4173). Shaded area represents time of CD4+ lymphocyte–depleting treatment.