Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

Abstract

Human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV)infection in macaques are accompanied by a combined early loss of CCR5 (CD195)-expressing CD4 + memory T cells, loss of T-helper function and T-cell hyperactivation, which have all been associated with development of high virus load and disease progression. Here, a cohort of vaccinated simian-human immunodeficiency virus strain 89.6p (SHIV 89.6p )-infected rhesus macaques, where preferential depletion of these memory T-cell subsets does not take place and CD4 + T cells are relatively well maintained, was used to study the role of hyperactivation as an independent factor in the establishment of set-point virus load. In the acute phase of the infection, a transient loss of CD4 + T cells, as well as strong increases in expression of proliferation and activation markers on CD4 + and CD8 + T cells, together with CD152 expression on CD4 + T cells, were observed. Peak expression levels of these markers on CD4 + T cells, but not on CD8 + T cells, were correlated with high virus replication in the chronic phase of the infection. In addition, the peak expression level of these markers was correlated inversely with acute-phase, but not chronic-phase, HIV/SIV-specific gamma interferon responses. These data highlight a central role for an acute but transient CD4 decrease, as well as CD4 + T-cell activation, as independent factors for prediction of set-point levels of virus replication. INTRODUCTIONHuman immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques are typically characterized by a slow, progressive loss of CD4 + T cells leading to immune incompetence and the onset of opportunistic infections (Fauci, 1988;Lifson et al., 1988). However, already by the early stages of infection, gut-homing CCR5-expressing CD4 memory subsets are being depleted (Brenchley et al., 2004;Li et al., 2005;Mattapallil et al., 2005Mattapallil et al., , 2004Veazey et al., 1998Veazey et al., , 2000 and CD4 + T-helper cell function is impaired (Clerici & Shearer, 1993; Koopman et al., 2001;Lane et al., 1985;McKay et al., 2003;Meyaard et al., 1996;Miedema et al., 1988;Shearer & Clerici, 1991). Recently, both events were found to be associated with the development of high virus load in SIVinfected macaques (Sun et al., 2007). Besides a possible direct immunosuppressive effect exerted by several HIV proteins (Cefai et al., 1992;Schindler et al., 2006;Westendorp et al., 1995), the formation of regulatory T cells, specifically the thymus-derived CD25 hi /FOXP3 + /CD152 + subset (Andersson et al., 2005;Estes et al., 2006;Hryniewicz et al., 2006;Kinter et al., 2004;Leng et al., 2002;Nilsson et al., 2006;Tsunemi et al., 2005), was found to be increased in HIV as well as in SIV infection, and was shown to contribute to suppression of HIV-specific immune responses (Kinter et al., 2004;Nilsson et al., 2006;Tsunemi et al., 2005).On the other hand, HIV infection induces a state of chronic immune activatio...

Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

“…Proliferation of both CD4+ and CD8+ T cells spiked 4 weeks after SIV infection (Figure S1), which closely mirrored the spike in plasma viremia (Figure 1). Similar elevations in CD4+ and CD8+ T cell proliferation were previously observed in blood, lymph nodes, and gut shortly after SIV infection (49–51). This burst of T cell proliferation corresponds to elevations in T cell apoptosis (50) and likely indicates a compensatory response to restore CD4+ T cell levels depleted by rampant viral replication, while simultaneously boosting CD8+ T cells, well-known antiviral effectors cells.…”

“…There was a transient spike in proliferation, as measured by ki-67, in CD4+ and CD8+ T cells at 4 weeks post-SIV infection which then subsided following ART to levels similar to those observed in uninfected macaques (Figure S1A, B). CD4+ and CD8+ T cell proliferation was previously shown to correspond to the rise in viral replication during acute SIV infection (49–51). Following Mtb infection, the frequency of PD-1+ CD4+ T cells, but not PD-1+ CD8+ T cells, declined significantly (Figure S1C, D).…”

Statins Increase the Frequency of Circulating CD4+FOXP3+Regulatory T Cells in Healthy Individuals

“…In agreement with the previous studies showing that statins suppressed CD25 upregulation by T cells [ 15 , 16 ], we also found decreased percentage of CD25 + cells within the CD4 + FOXP3 + population at all time points compared to baseline ( Figure 2(c) ). We also examined Ki-67 expression by Treg because Ki-67 induction is a marker of cell activation/proliferation [ 17 , 18 ]. We found reduced expression of Ki-67 by Treg in treated individuals, while it did not significantly change over time in total CD4 + T cells (Figures 3(a) and 3(b) ).…”

Potent Immune Responses in Rhesus Macaques Induced by Nonviral Delivery of a Self-amplifying RNA Vaccine Expressing HIV Type 1 Envelope With a Cationic Nanoemulsion

“…Quantification of antigen-specific cytokine-secreting cells was performed on freshly isolated PBMCs by interferon γ (IFN-γ), interleukin 2 (IL-2), and interleukin 4 (IL-4) ELISPOT assays, as described elsewhere [45]. Separate peptide pools, consisting of 15mers with an 11-amino acid overlap, that covered the entire gp120 of ConS, gp41 ConS, or gp120 TV1 protein were used to measure antigen-specific immune responses after each immunization.…”