Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Sep 15;185(6):3348-58.
doi: 10.4049/jimmunol.1000572. Epub 2010 Aug 11.

Emergence of simian immunodeficiency virus-specific cytotoxic CD4+ T cells and increased humoral responses correlate with control of rebounding viremia in CD8-depleted macaques infected with Rev-independent live-attenuated simian immunodeficiency virus

Agneta von Gegerfelt  1 , Antonio Valentin, Candido Alicea, Koen K A Van Rompay, Marta L Marthas, David C Montefiori, George N Pavlakis, Barbara K Felber
Affiliations

Emergence of simian immunodeficiency virus-specific cytotoxic CD4+ T cells and increased humoral responses correlate with control of rebounding viremia in CD8-depleted macaques infected with Rev-independent live-attenuated simian immunodeficiency virus

Agneta von Gegerfelt et al. J Immunol. .

Abstract

Indian rhesus macaques infected with the Rev-independent live-attenuated SIVmac239 strains control viremia to undetectable levels, have persistent but low cellular and humoral anti-SIV responses, and show no signs of immune deficiency. To analyze the immune mechanisms responsible for viral control, five macaques infected at day 1 after birth were subjected to CD8(+) cell depletion at 6.7 y postinfection. This resulted in viremia increases to 3.7-5.5 log(10) RNA copies, supporting a role of CD8-mediated responses in the control of viral replication. The rebounding viremia was rapidly controlled to levels below the threshold of detection, and occurred in the absence of SIV-specific CD8(+) T cells and significant CD8(+) T cell recovery in four of the five animals, suggesting that other mechanisms are involved in the immunological control of viremia. Monitoring immune responses at the time of viral control demonstrated a burst of circulating SIV-specific CD4(+) T cells characterized as CD45RA(-)CD28(+)CD95(+)CCR7(-) and also granzyme B(+), suggesting cytotoxic ability. Control of viremia was also concomitant with increases in humoral responses to Gag and Env, including a transient increase in neutralizing Abs against the neutralization-resistant SIVmac239 in four of five animals. These data demonstrate that a combination of cellular responses mediated by CD4(+) T cells and humoral responses was associated with the rapid control of the rebounding viremia in macaques infected by the Rev-independent live-attenuated SIV, even in the absence of measurable SIV-specific CD8(+) T cells in the blood, emphasizing the importance of different components of the immune response for full control of SIV infection.

PubMed Disclaimer

Conflict of interest statement

Disclosures

The authors have no financial conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Rev-independent SIV strains with attenuated growth properties. A, Molecular clones of the Rev-independent SIVmac239. All viruses have multiple point mutations destroying rev and RRE, designed to preserve the coding potential of the overlapping tat and env coding regions (–13). The clone Rev−RRE−Nef−CTEIAP+ contains the CTEIAP inserted 3′ to the terminator of env, which renders this clone nef-minus (13). The clone Rev−RRE−Nef+CTE+ contains the SRV-1 CTE and has the 5′ portion of nef(nt 9081–9280) inserted 3′ to the CTE, generating an intact nef open reading frame. B, The Rev-independent LASIV-infected animals were monitored over time. The plasma virus loads are shown over 6.7 y of infection up to the day of enrollment of the CD8 depletion study. Note that the threshold of the assays changed over the years of follow-up. The follow-up to 5.9 y postinfection has been reported previously (12). CTEIAP; CTE from the murine IAP retroelement.
FIGURE 2.
FIGURE 2.
Changes in CD8+ T cells and viral loads after treatment with cM-T807 Ab. A, Macaques were subjected to CD8+ cell depletion 6.7 y postinfection with the Rev-independent SIVmac239 strains. A single treatment with the cM-T807 Ab led to temporal depletion of CD8+ lymphocytes and transient loss of control of viremia. The CD3+CD8+ T cell counts (measured with the anti-CD8 Ab DK25) per μl of blood (gray line) and plasma viral loads (black line) were monitored over time. B, Measurements of circulating CD4+ T cells of the five animals subjected to CD8+ cell depletion.
FIGURE 3.
FIGURE 3.
Frequency of CD8+ cells within the T lymphocyte population measured by flow cytometry. A, T lymphocytes were gated according to a scatter (left) and CD3 staining (right). B, Dot plots show the frequency of circulating CD8+ and CD4+ cells within gated CD3+ T cell population upon CD8+ lymphocyte depletion. The five macaques were monitored at the day of depletion and at weeks 1, 4, 8, and 33 postdepletion. Numbers represent the percentage of these two cell populations among the total CD3+ T lymphocytes.
FIGURE 4.
FIGURE 4.
SIV-specific cellular immune responses induced upon CD8+ depletion. Analysis of blood samples collected 4 wk prior to depletion, at the day of depletion, and at weeks 1, 3, 4, 6 (animal 31470), 8, and 33 postdepletion is shown. A, The frequency of SIV-specific CD4+ (light gray bar) and CD8+ (black bar) T cells was measured in PBMCs by multicolor flow cytometry after in vitro stimulation with Gag (left panel) or Env (right panel) peptide pools, followed by intracellular staining for IFN-γ. Note the variable scales for the different animals. Arrow indicate the time of peak viremia. B, Viral loads and changes in the frequency of SIV-specific CD4+ T lymphocytes after depletion with the cM-T807 Ab. In all five animals, control of viremia coincides with a peak of Ag-specific CD4+ T cells.
FIGURE 5.
FIGURE 5.
Phenotypic analysis of the SIV-specific T cells. A, Memory phenotype of the SIV-specific (Gag and Env) T cells upon CD8 depletion. The T cells were divided in CD3+CD28+CD45RA− and CD3+CD28−. The two subsets were further divided in CD4+ and CD8+ populations. B, Overlays showing the pattern of expression of the SIV-specific T cells (blue) and the general T cell population (red) for CD95 and CD28 (left panels) and CCR7 and granzyme B (right panels) at the time of control of rebounding virus (week 3 for four of the animals, and week 6 for macaque 31470). #, sample not analyzed for Env responses; n/a, sample not available.
FIGURE 6.
FIGURE 6.
Frequency of granzyme B+ cells among the Gag-specific (left panels) or Env-specific (right panels) T lymphocytes at the time of control of rebounding viremia (week 6 for animal 31470, and week 3 for the other four macaques). Numbers in the plots denote the percentage of granzyme B+ included in the displayed gates.
FIGURE 7.
FIGURE 7.
Increase in SIV-specific humoral immune responses after CD8+ lymphocyte depletion. Reciprocal log Ab titers to SIV Gag (open circles) and Env (black circles), respectively, were defined as the plasma dilution at or above two times the absorbance values of the naive controls. Plasma samples below the cutoff value of dilution 1/20 are shown in the graph as log 1. Ab titers for Gag and Env for the five animals and the SIV viral loads (from Fig. 1, gray lane) are shown. Note the different scale of the x-axis for animal 31470.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Koff WC, Johnson PR, Watkins DI, Burton DR, Lifson JD, Hasenkrug KJ, McDermott AB, Schultz A, Zamb TJ, Boyle R, and Desrosiers RC. 2006. HIV vaccine design: insights from live attenuated SIV vaccines. Nat. Immunol 7: 19–23. - PubMed
    1. Whitney JB, and Ruprecht RM. 2004. Live attenuated HIV vaccines: pitfalls and prospects. Curr. Opin. Infect. Dis 17: 17–26. - PubMed
    1. Blancou P, Chenciner N, Ho Tsong Fang R, Monceaux V, Cumont MC, Guétard D, Hurtrel B, and Wain-Hobson S. 2004. Simian immunodeficiency virus promoter exchange results in a highly attenuated strain that protects against uncloned challenge virus. J. Virol 78: 1080–1092. - PMC - PubMed
    1. Desrosiers RC, Lifson JD, Gibbs JS, Czajak SC, Howe AY, Arthur LO, and Johnson RP. 1998. Identification of highly attenuated mutants of simian immunodeficiency virus. J. Virol 72: 1431–1437. - PMC - PubMed
    1. Fultz PN,Vance PJ, Endres MJ,Tao B, Dvorin JD, Davis IC, Lifson JD, Montefiori DC, Marsh M, Malim ΜH, and Hoxie JA. 2001. In vivo attenuation of simian immunodeficiency virus by disruption of a tyrosine-dependent sorting signal in the envelope glycoprotein cytoplasmic tail. J. Virol 75: 278–291. - PMC - PubMed

Publication types

MeSH terms