JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Low CD4+ T-Cell Surface CCR5 Density as a Cause of Resistance to In Vivo HIV-1 Infection
Reynes, Jacques; Baillat, Vincent; Portales, Pierre; Clot, Jacques; Corbeau, Pierre
From the Service des Maladies Infectieuses
et Tropicales, Hôpital Gui de Chauliac
(Drs Reynes and Baillat)
Laboratoire d'Immunologie, Hôpital
Saint Eloi (Drs Portales, Clot, and Corbeau)
Institut de Génétique Humaine CNRS
UPR114Z Montpellier, France (Dr Corbeau)
To the Editor:
We have recently shown that the mean number of CCR5 coreceptors at the surface of CD4+ cells strongly determines the efficiency of HIV-1 life cycle in vitro. 1 For this reason, we have tested the hypothesis that low CD4+ T-cell surface CCR5 density could favor resistance to HIV-1 infection in vivo. For this purpose, using a quantitative flow cytometry assay, 2 we measured CCR5 expression in 24 HIV-1-seronegative adults (14 men and 10 women) with multiple high-risk sexual exposures to HIV-1. Figure 1 shows that exposed uninfected subjects expressed low CCR5 densities (arithmetics means of 9273 [95% CI, 7661–10,885] CCR5 molecules per cell) compared with 84 sex-matched nonexposed control HIV-negative individuals (arithmetics means of 11,145 [95% CI, 10,379–11,911]P = 0.05).
As we have previously shown that CD4+ T-cell surface CCR5 density is stable over time for a given individual, 2 these results argue for the fact that low CCR5 expression could participate, in addition to virologic factors, to immune responses or to antiviral factors produced by CD8+ T cells in the resistance to HIV-1 infection. 3 They also explain why subjects heterozygous for the CCR5 32 base-pair deletion (Δ32) allele, who express low CCR5 densities, 4 might be more resistant to HIV-1 infection. 5,6 Moreover, our data are consistent with previous works reporting, in conflict with others, 7 that CD4+ T cells from some exposed uninfected subjects are less susceptible to HIV-1 infection 8,9 and that these CD4+ T cells show low surface expression of CCR5. 8,10
Our data further emphasize the key role played in HIV-1 infection by CD4+ T-cell surface CCR5 density, which influences in vivo infectibility (this work), virus load, 2 disease progression, 11 and response to treatment. 12
1. Lin Y-L, Mettling C, Portales P, et al. Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. Proc Natl Acad Sci U S A. 2002; 99:15590–15595.
2. Reynes J, Portales P, Segondy M, et al. CD4+ T cell surface CCR5 density as a determining factor of viral load in HIV-1-infected individuals. J Infect Dis. 2000; 181:927–932.
3. Paxton WA, Koup RA. Mechanisms of resistance to HIV infection. Springer Semin Immunopathol. 1997; 18:323–340.
4. Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996; 86:367–377.
5. Michael NL, Chang G, Louie LG, et al. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med. 1997; 3:338–340.
6. Marmor M, Sheppard HW, Donnell D, et al. Homozygous and heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV infection. J Acquir Immune Defic Syndr. 2001; 15:472–481.
7. Fowke KR, Dong T, Rowland-Jones SL, et al. HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced β-chemokine production. AIDS Res Hum Retroviruses. 1998; 14:1521–1530.
8. Paxton WA, Liu R, Kang S, et al. Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of β-chemokines. Virology. 1998; 244:66–73.
9. Blaak H, van't Wout AB, Brouwer M, et al. Infectious cellular load in Human Immunodeficiency Virus type 1 (HIV-1)-infected individuals and susceptibility of peripheral blood mononuclear cells from their exposed partners to non-syncytium-inducing HIV-1 as major determinants for HIV-1 transmission in homosexual couples. J Virol. 1998; 72:218–224.
10. Paxton WA, Kang S, Liu R, et al. HIV-1 infectability of CD4+ lymphocytes with relation to beta-chemokines and the CCR5 coreceptor. Immunol Lett. 1999; 66:71–75.
11. Reynes J, Portales P, Segondy M, et al. CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. AIDS. 2001; 15:1627–1634.
12. Gervaix A, Nicolas J, Portales P, et al. Response to treatment and disease progression linked to CD4+ T cell surface CCR5 density in HIV-1 vertical infection. J Infect Dis. 2002; 185:1055–1061.
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