Downregulation of CCR5 on activated CD4 T cells in HIV-infected Indians

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Abstract

Background

HIV infection in India is unique as it occurs predominantly by CCR5-utilizing isolates that exhibit no co-receptor switch.

Objectives

To study HIV-1 co-receptor dynamics on T cells and monocytes following viral infection.

Study design

HIV co-receptor expression was evaluated by flow cytometry on various cell subsets in HIV-infected Indians and in vitro in human peripheral blood mononuclear cells infected with CCR5- or CXCR4-utilizing HIV-1. Transfection of the T cell line CEM-CCR5 (which expresses CD4, CCR5 and CXCR4) with HIV-1 Nef or Vpu expression vectors, or treatment with recombinant soluble gp120 from CCR5- and CXCR4-tropic HIV-1, was carried out to determine their effects on co-receptor expression.

Results

Indian HIV patients had fewer CD4+CCR5+ T cells and CCR5-expressing activated CD4+ T cells, but higher CXCR4-expressing activated CD4+ T cells compared with controls. Expression of CCR5 was not different on monocytes in HIV patients as compared to controls. The CCR5 downregulation on T cells was HIV infection specific and was governed by the co-receptor-utilization phenotype of the virus. The Nef and soluble gp120 proteins induced CCR5 downregulation, the latter in a co-receptor-utilization phenotype specific manner.

Conclusions

The HIV-1 co-receptor dynamics in Indian patients is distinct from western patients and depends upon the virus surface protein. We propose this to be a viral survival strategy.

Introduction

Chemokine receptors regulate trafficking of immune cells to sites of inflammation (Springer, 1994, Oppermann, 2004) The chemokine receptors CCR5 and CXCR4 have been identified as principal co-receptors for macrophage-tropic (R5) and T cell-tropic (X4) HIV-1 isolates, respectively (Berger et al., 1999). While HIV-1 strains that initiate infection are predominantly macrophage-tropic, during its natural evolution in the host the virus switches its co-receptor preference late in infection from CCR5-utilizing (R5) to CXCR4-utilizing (X4) strains. This is associated with an expanded target cell range and worsening prognosis (Regoes and Bonhoeffer, 2005). The CCR5 and CXCR4 proteins are expressed on known cell and tissue targets of HIV-1, consistent with their roles in disease transmission and progression. The expression of CCR5 and CXCR4 is also observed in a reciprocal manner on T cells; naïve resting T cells predominantly express CXCR4, while CCR5 is expressed on activated or memory T cells (Bleul et al., 1997).

Studies on co-receptor expression in HIV-infected persons from western countries show an increase in CCR5 expression on CD4 T cells (Ostrowski et al., 1998) and a restoration in CCR5 levels on these cells after HAART (Pierdominici et al., 2002, Brito et al., 2007). Data from African countries indicate high pre-existing levels of CCR5 on CD4 T cells in HIV-uninfected individuals (Clerici et al., 2000). Therefore, selection of the predominant virus strain within the population could be influenced by the pattern of HIV co-receptor expression. In the Indian population, HIV-1 infection occurs predominantly by subtype C isolates which exhibit no switch in co-receptor usage during the late phase of infection and disease (Cecilia et al., 2000). This is also the case with non-subtype C isolates from India. We therefore asked whether prevalence of only CCR5-utilizing strains and absence of co-receptor switch is a consequence of altered co-receptor dynamics in Indian patients.

Section snippets

Subjects

The study population consisted of 40 HIV-seropositive, treatment naïve patients (30 males and 10 females; age 35 ± 9.1 yr) attending the Immunodeficiency Clinic at Postgraduate Institute for Medical Education and Research (PGIMER), Chandigarh, India. For comparison, 22 healthy HIV-seronegative controls (16 males and 6 females; age 28 ± 5 yr) comprised of residents and laboratory workers were also studied. The clinical classification was based on the CDC 1993 revised guidelines. Seropositivity was

Co-receptor expression on T cells in HIV-infected Indians

The numbers of CD4+ and CD4+CCR5+ T cells in patients were reduced as compared to controls (Fig. 1A). The expression levels of CCR5 on CD4+ T cells were comparable in HIV-infected patients and controls (Fig. 1B). While there was no increase in the numbers of CD4+CXCR4+ T cells (Fig. 1A), the levels of CXCR4 on CD4+ T cells were elevated in patients compared to controls (Fig. 1B). The CD8+CCR5+ subset was also reduced in patients compared to controls, but there was no change in the CD8+CXCR4+

Discussion

We found markedly reduced numbers of CCR5-expressing activated CD4 T cells and increased numbers of CXCR4-expressing cells in HIV-infected Indians. While there was no difference in the levels of CXCR4, the expression levels of surface CCR5 on these cells were markedly reduced. In contrast to our results, CXCR4 downregulation and CCR5 upregulation was observed on activated CD4 T cells from western HIV-infected persons (Ostrowski et al., 1998). The expression levels of CXCR4 were found to be

Acknowledgements

We thank the NIH AIDS Research and Reference Reagent Program for various cell lines and virus clones, Dr. R. Varadarajan (Indian Institute of Science, Bangalore) for the recombinant HIV-1 JR-FL gp120 and the Department of Biotechnology (DBT), Government of India for funding.

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