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J Virol. Dec 2006; 80(24): 12425–12429.
Published online Oct 11, 2006. doi:  10.1128/JVI.01557-06
PMCID: PMC1676275

Increased Frequency of Circulating CCR5+ CD4+ T Cells in Human Immunodeficiency Virus Type 2 Infection[down-pointing small open triangle]

Abstract

CCR5 expression determines susceptibility to infection, cell tropism, and the rate of human immunodeficiency virus type 1 (HIV-1) disease progression. CCR5 is also considered the major HIV-2 coreceptor in vivo, in spite of broad coreceptor use in vitro. Here we report a significantly increased proportion of memory-effector CD4 T cells expressing CCR5 in HIV-2-infected patients correlating with CD4 depletion. Moreover, HIV-2 proviral DNA was essentially restricted to memory-effector CD4, suggesting that this is the main target for HIV-2. Similar levels of proviral DNA were found in the two infection categories. Thus, the reduced viremia and slow rate of CD4 decline that characterize HIV-2 infection seem to be unrelated to coreceptor availability.

Human immunodeficiency virus type 2 (HIV-2) immunodeficiency is characterized by slow disease progression with limited impact on the survival of the majority of infected adults (20, 33, 45). The rate of CD4+ T-cell decline is much slower in HIV-2 than in HIV-1 disease, and there is a low plasma viral load irrespective of disease stage (2, 4, 9, 17, 20, 32, 41, 43). The factors contributing to the suggested decreased rate of virus production in HIV-2 infection remain largely unknown.

In spite of the promiscuity of coreceptor usage exhibited by HIV-2 in in vitro experimental settings (8, 13, 16, 22, 29, 39, 40), several lines of evidence show that CCR5 and CXCR4 are the major coreceptors for HIV-2 infection in vivo (6, 24, 25).

In HIV-1-infected patients, CCR5 expression determines susceptibility to infection, cell tropism, and the rate of disease progression and is currently an important target of new antiretroviral drugs (10, 11, 21, 27, 34, 35).

There are scanty data available on CCR5 and CXCR4 expression in HIV-2-infected patients. A previous study of a Senegalese cohort reported lower CCR5 expression in HIV-2 than in HIV-1 infection, but as these patients, unlike our cohorts, were not stratified according to CD4 depletion or viremia, direct comparison is problematic (38).

We analyzed here CCR5 and CXCR4 expression in freshly isolated peripheral blood mononuclear cells (PBMC) from untreated HIV-2- and HIV-1-infected subjects who were currently living in Portugal and attending outpatient clinics in Lisbon and who exhibited no known ongoing opportunistic infections or tumors. The epidemiological and clinical features of these cohorts, as well as of healthy controls, are summarized in Table Table1.1. Of note, HIV-2 and HIV-1 cohorts exhibited similar levels of CD4 depletion but striking differences in viremia.

TABLE 1.
Cohort characterization

CCR5 and CXCR4 expression were assessed by flow cytometry in freshly isolated PBMC as previously described (42).

HIV-2-positive patients exhibited a higher frequency of CCR5+ cells within the CD4+ subset that reaches statistical significance than that seen with healthy subjects (Fig. (Fig.1A).1A). In HIV-2 patients CCR5 expression was also largely confined to the memory CD4+ CD45RA population, as illustrated in the representative contour plot of Fig. Fig.1B1B.

FIG. 1.
CCR5 and CXCR4 expression in circulating CD4+ T cells from HIV-2- and HIV-1-infected patients as well as healthy controls. Freshly isolated PBMC were surface stained with anti-CCR5 (clone 2D7) or anti-CXCR4 (clone 12G5) monoclonal antibodies (phycoerythrin ...

The frequencies of CXCR4+ cells within CD4 T cells showed no significant differences among the three cohorts, although there was a trend to lower frequencies in the HIV-2 cohort in both the naïve and memory subsets (Fig. (Fig.1C1C).

A significant correlation between the frequency of CCR5+ cells within the CD4 subset and the degree of CD4 depletion was observed with the HIV-2 cohort that was not observed with HIV-1-positive patients (Fig. (Fig.1D1D).

We have previously shown that CD4 depletion is directly linked to immune activation in both HIV-2 and HIV-1 infections in spite of the striking differences in viremia (15, 42). Since CCR5 is up-regulated upon T-cell activation, we looked for a possible correlation between the frequency of CCR5+ cells and the expression of HLA-DR, a marker widely used to quantify immune activation in HIV disease (15). A significant correlation was observed with the HIV-2 cohort (r = 0.68; P = 0.0009) that was not found with HIV-1-positive patients (r = 0.25; P = 0.2814).

These data illustrated the link between the expansion of CCR5+ cells and immune activation in HIV-2 infection. The lower frequency of circulating CCR5+ cells in HIV-1 infection compared to HIV-2 results despite the similarities in heightened immune activation may be related to a continuous depletion of the CCR5 pool in association with the high level of viremia (19, 23).

The frequency of CCR5+ cells may be underestimated due to binding-induced receptor internalization (26, 30). In fact, the assessment of the median fluorescence intensity (MedianFI) of CCR5+ CD4+ T cells revealed similar and significant down-regulation results for both HIV-2- and HIV-1-infected cohorts in comparison with the results seen with healthy subjects (Fig. (Fig.1E).1E). This contrasts with the absence of differences in MedianFI of CXCR4+ CD4+ T cells for the three cohorts (Fig. (Fig.1F).1F). It is noteworthy that HIV-2 infection has been associated with high levels of production of RANTES, MIP-1α, and MIP-1β (1, 18, 28), possibly contributing to the CCR5 down-regulation.

In order to exclude the possibility that CCR5Δ32 mutations contribute to the low MedianFI of CCR5 (44), we screened the cohorts for the presence of this allele using the primers described in Table Table2.2. None of the HIV-2- or HIV-1-infected patients exhibited the CCR5Δ32 allele. There were five healthy subjects heterozygous for CCR5Δ32. The exclusion of these individuals from the analysis resulted in an even more significant difference in the results of down-regulation of CCR5 MedianFI between HIV cohorts and healthy subjects (P = 0.0019 for HIV-2 and P < 0.0001 for HIV-1).

TABLE 2.
Primer and probe sequencesa

On the other hand, despite differing levels of viremia, we did not find significant differences between HIV-2 and HIV-1 proviral DNA levels, suggesting the presence of similar numbers of infected cells in the two infection categories (Table (Table1),1), in agreement with previous reports (3-5, 14, 31). Proviral DNA was assessed by absolute quantitative real-time PCR using an ABI PRISM 7000 sequence detection system (Applied Biosystems) with a detection range of 7 orders of magnitude and a sensitivity of five copies. Reactions containing 150 ng of genomic DNA extracted from 106 PBMC by use of an ABI PRISM 6100 nucleic acid extractor (Applied Biosystems), 25 μl of Platinum quantitative PCR SuperMix-UDG, 1 μl ROX reference dye (Invitrogen) (50×), 5 mM MgCl2, 300 nM primer (each), and 200 nM probe (Table (Table2)2) were run in duplicate. Albumin was used to standardize DNA input.

It is worth noting that no correlation was found between the frequency of CCR5+ cells within the CD4 subset and the levels of HIV-2 proviral DNA (r = 0.08; P = 0.7483).

In order to evaluate the possibility that the similar levels of proviral DNA in the presence of the dissimilar HIV-1 and HIV-2 viremia results might be due to differences in cell targets, we purified the naïve and the memory CD4 T cells from PBMC of two HIV-2 patients with different levels of CD4 depletion by high-speed cell sorting using FACSAria (BD Biosciences).

As depicted in Table Table3,3, the levels of HIV-2 proviral DNA documented in the naïve subset were minimal. Therefore, these data suggest that memory CD4 T cells are the main targets for HIV-2 infection in vivo, reinforcing the idea of a major role of CCR5 coreceptor in HIV-2 infection. This was in agreement with data on HIV-1 infection in which integrated proviruses are preferentially detected within the memory subset (7, 12, 36).

TABLE 3.
HIV-2 proviral DNA in CD4 naïve and memory subsets

In summary, HIV-2-infected patients showed an increase in the proportion of CCR5+ cells within the memory-effector CD4+ T cells in correlation with the degree of CD4 depletion and immune activation. In contrast, in HIV-1 infection there was dissociation between CCR5 and other markers of immune activation which could be interpreted as an indirect evidence of depletion of the CCR5+ cells by HIV-1. However, the HIV-2 proviral load was also mainly restricted to memory-effector CD4 T cells, suggesting these are the major HIV-2 targets, which is consistent with CCR5 being the main HIV-2 coreceptor in vivo. Moreover, the levels of HIV-2 proviral load were similar to those observed in untreated HIV-1-infected individuals, suggesting equivalent numbers of infected cells resulting from the two diseases in spite of viremia being undetectable in the majority of the HIV-2 patients.

The presence of reduced HIV-2 viremia seems to be unrelated to coreceptor availability. Since HIV-2 is no less cytopathic per se than HIV-1 (37), other host factors must be implicated in the control of viral replication in spite of significant proviral DNA levels in HIV-2-positive patients. The further investigation of the mechanisms contributing to this control of HIV-2 viremia in the absence of antiretroviral therapy may prove to be useful in defining complementary therapeutic strategies to control viral reservoirs in HIV-1.

Acknowledgments

This work was supported by grants from Fundação para a Ciência e a Tecnologia (FCT) and Comissão Nacional de Luta Contra a SIDA to A.E.S. R.S., R.F., and C.C. received scholarships from FCT.

We gratefully acknowledge Perpétua Gomes for the quantification of HIV-2 viremia, Ana Caetano for cell sorting technical assistance, and the clinical collaboration of the following colleagues: E. Valadas, F. Antunes, L. Pinheiro, M. Doroana, M. Lucas, and R. Marçal.

Footnotes

[down-pointing small open triangle]Published ahead of print on 11 October 2006.

REFERENCES

1. Ahmed, R. K., H. Norrgren, Z. da Silva, A. Blaxhult, E. L. Fredriksson, G. Biberfeld, S. Andersson, and R. Thorstensson. 2005. Antigen-specific beta-chemokine production and CD8 T-cell noncytotoxic antiviral activity in HIV-2-infected individuals. Scand. J. Immunol. 61:63-71. [PubMed]
2. Andersson, S., H. Norrgren, Z. da Silva, A. Biague, S. Bamba, S. Kwok, C. Christopherson, G. Biberfeld, and J. Albert. 2000. Plasma viral load in HIV-1 and HIV-2 singly and dually infected individuals in Guinea-Bissau, West Africa: significantly lower plasma virus set point in HIV-2 infection than in HIV-1 infection. Arch. Intern. Med. 160:3286-3293. [PubMed]
3. Ariyoshi, K., N. Berry, A. Wilkins, D. Ricard, P. Aaby, A. Naucler, P. T. Ngom, O. Jobe, S. Jaffar, F. Dias, R. S. Tedder, and H. Whittle. 1996. A community-based study of human immunodeficiency virus type 2 provirus load in rural village in West Africa. J. Infect. Dis. 173:245-248. [PubMed]
4. Berry, N., K. Ariyoshi, S. Jaffar, S. Sabally, T. Corrah, R. Tedder, and H. Whittle. 1998. Low peripheral blood viral HIV-2 RNA in individuals with high CD4 percentage differentiates HIV-2 from HIV-1 infection. J. Hum. Virol. 1:457-468. [PubMed]
5. Berry, N., K. Ariyoshi, O. Jobe, P. T. Ngum, T. Corrah, A. Wilkins, H. Whittle, and R. Tedder. 1994. HIV type 2 proviral load measured by quantitative polymerase chain reaction correlates with CD4+ lymphopenia in HIV type 2-infected individuals. AIDS Res. Hum. Retrovir. 10:1031-1037. [PubMed]
6. Blaak, H., P. H. Boers, R. A. Gruters, H. Schuitemaker, M. E. van der Ende, and A. D. Osterhaus. 2005. CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia. J. Virol. 79:1686-1700. [PMC free article] [PubMed]
7. Brenchley, J. M., B. J. Hill, D. R. Ambrozak, D. A. Price, F. J. Guenaga, J. P. Casazza, J. Kuruppu, J. Yazdani, S. A. Migueles, M. Connors, M. Roederer, D. C. Douek, and R. A. Koup. 2004. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J. Virol. 78:1160-1168. [PMC free article] [PubMed]
8. Bron, R., P. J. Klasse, D. Wilkinson, P. R. Clapham, A. Pelchen-Matthews, C. Power, T. N. Wells, J. Kim, S. C. Peiper, J. A. Hoxie, and M. Marsh. 1997. Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. J. Virol. 71:8405-8415. [PMC free article] [PubMed]
9. Damond, F., M. Gueudin, S. Pueyo, I. Farfara, D. L. Robertson, D. Descamps, G. Chène, S. Matheron, P. Campa, F. Brun-Vézinet, and F. Simon. 2002. Plasma RNA viral load in human immunodeficiency virus type 2 subtype A and subtype B infections. J. Clin. Microbiol. 40:3654-3659. [PMC free article] [PubMed]
10. Dean, M., M. Carrington, C. Winkler, G. A. Huttley, M. W. Smith, R. Allikmets, J. J. Goedert, S. P. Buchbinder, E. Vittinghoff, E. Gomperts, S. Donfield, D. Vlahov, R. Kaslow, A. Saah, C. Rinaldo, R. Detels, and S. J. O'Brien. 1996. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856-1862. [PubMed]
11. de Roda Husman, A. M., H. Blaak, M. Brouwer, and H. Schuitemaker. 1999. CC chemokine receptor 5 cell-surface expression in relation to CC chemokine receptor 5 genotype and the clinical course of HIV-1 infection. J. Immunol. 163:4597-4603. [PubMed]
12. Douek, D. C., J. M. Brenchley, M. R. Betts, D. R. Ambrozak, B. J. Hill, Y. Okamoto, J. P. Casazza, J. Kuruppu, K. Kunstman, S. Wolinsky, Z. Grossman, M. Dybul, A. Oxenius, D. A. Price, M. Connors, and R. A. Koup. 2002. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95-98. [PubMed]
13. Endres, M. J., P. R. Clapham, M. Marsh, M. Ahuja, J. D. Turner, A. McKnight, J. F. Thomas, B. Stoebenau-Haggarty, S. Choe, P. J. Vance, T. N. Wells, C. A. Power, S. S. Sutterwala, R. W. Doms, N. R. Landau, and J. A. Hoxie. 1996. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 87:745-756. [PubMed]
14. Gomes, P., N. C. Taveira, J. M. Pereira, F. Antunes, M. O. Ferreira, and M. H. Lourenco. 1999. Quantitation of human immunodeficiency virus type 2 DNA in peripheral blood mononuclear cells by using a quantitative-competitive PCR assay. J. Clin. Microbiol. 37:453-456. [PMC free article] [PubMed]
15. Grossman, Z., M. Meier-Schellersheim, A. E. Sousa, R. M. Victorino, and W. E. Paul. 2002. CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat. Med. 8:319-323. [PubMed]
16. Guillon, C., M. E. van der Ende, P. H. Boers, R. A. Gruters, M. Schutten, and A. D. Osterhaus. 1998. Coreceptor usage of human immunodeficiency virus type 2 primary isolates and biological clones is broad and does not correlate with their syncytium-inducing capacities. J. Virol. 72:6260-6263. [PMC free article] [PubMed]
17. Jaffar, S., A. Wilkins, P. T. Ngom, S. Sabally, T. Corrah, J. E. Bangali, M. Rolfe, and H. C. Whittle. 1997. Rate of decline of percentage CD4+ cells is faster in HIV-1 than in HIV-2 infection. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 16:327-332. [PubMed]
18. Kokkotou, E. G., J. L. Sankale, I. Mani, A. Gueye-Ndiaye, D. Schwartz, M. E. Essex, S. Mboup, and P. J. Kanki. 2000. In vitro correlates of HIV-2-mediated HIV-1 protection. Proc. Natl. Acad. Sci. USA 97:6797-6802. [PMC free article] [PubMed]
19. Krzysiek, R., A. Rudent, L. Bouchet-Delbos, A. Foussat, C. Boutillon, A. Portier, D. Ingrand, D. Sereni, P. Galanaud, L. Grangeot-Keros, and D. Emilie. 2001. Preferential and persistent depletion of CCR5+ T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infection. Blood 98:3169-3171. [PubMed]
20. Marlink, R., P. Kanki, I. Thior, K. Travers, G. Eisen, T. Siby, I. Traore, C. C. Hsieh, M. C. Dia, E. H. Gueye, J. Hellinger, A. Gueye-Ndiaye, J. L. Sankalé, I. Ndoye, S. Mboup, and M. Essex. 1994. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 265:1587-1590. [PubMed]
21. Martin, M. P., M. Dean, M. W. Smith, C. Winkler, B. Gerrard, N. L. Michael, B. Lee, R. W. Doms, J. Margolick, S. Buchbinder, J. J. Goedert, T. R. O'Brien, M. W. Hilgartner, D. Vlahov, S. J. O'Brien, and M. Carrington. 1998. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 282:1907-1911. [PubMed]
22. McKnight, A., M. T. Dittmar, J. Moniz-Periera, K. Ariyoshi, J. D. Reeves, S. Hibbitts, D. Whitby, E. Aarons, A. E. Proudfoot, H. Whittle, and P. R. Clapham. 1998. A broad range of chemokine receptors are used by primary isolates of human immunodeficiency virus type 2 as coreceptors with CD4. J. Virol. 72:4065-4071. [PMC free article] [PubMed]
23. Mehandru, S., M. A. Poles, K. Tenner-Racz, A. Horowitz, A. Hurley, C. Hogan, D. Boden, P. Racz, and M. Markowitz. 2004. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200:761-770. [PMC free article] [PubMed]
24. Morner, A., A. Bjorndal, J. Albert, V. N. Kewalramani, D. R. Littman, R. Inoue, R. Thorstensson, E. M. Fenyo, and E. Bjorling. 1999. Primary human immunodeficiency virus type 2 (HIV-2) isolates, like HIV-1 isolates, frequently use CCR5 but show promiscuity in coreceptor usage. J. Virol. 73:2343-2349. [PMC free article] [PubMed]
25. Morner, A., A. Bjorndal, A. C. Leandersson, J. Albert, E. Bjorling, and M. Jansson. 2002. CCR5 or CXCR4 is required for efficient infection of peripheral blood mononuclear cells by promiscuous human immunodeficiency virus type 2 primary isolates. AIDS Res. Hum. Retrovir. 18:193-200. [PubMed]
26. Mueller, A., E. Kelly, and P. G. Strange. 2002. Pathways for internalization and recycling of the chemokine receptor CCR5. Blood 99:785-791. [PubMed]
27. Mummidi, S., S. S. Ahuja, E. Gonzalez, S. A. Anderson, E. N. Santiago, K. T. Stephan, F. E. Craig, P. O'Connell, V. Tryon, R. A. Clark, M. J. Dolan, and S. K. Ahuja. 1998. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat. Med. 4:786-793. [PubMed]
28. Neoh, L. P., H. Akimoto, H. Kaneko, T. Hishikawa, H. Hashimoto, S. Hirose, Y. Kaneko, N. Yamamoto, and I. Sekigawa. 1997. The production of beta-chemokines induced by HIV-2 envelope glycoprotein. AIDS 11:1062-1063. [PubMed]
29. Owen, S. M., D. Ellenberger, M. Rayfield, S. Wiktor, P. Michel, M. H. Grieco, F. Gao, B. H. Hahn, and R. B. Lal. 1998. Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry. J. Virol. 72:5425-5432. [PMC free article] [PubMed]
30. Pastori, C., B. Weiser, C. Barassi, C. Uberti-Foppa, S. Ghezzi, R. Longhi, G. Calori, H. Burger, K. Kemal, G. Poli, A. Lazzarin, and L. Lopalco. 2006. Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression. Blood 107:4825-4833. [PMC free article] [PubMed]
31. Popper, S. J., A. D. Sarr, A. Gueye-Ndiaye, S. Mboup, M. E. Essex, and P. J. Kanki. 2000. Low plasma human immunodeficiency virus type 2 viral load is independent of proviral load: low virus production in vivo. J. Virol. 74:1554-1557. [PMC free article] [PubMed]
32. Popper, S. J., A. D. Sarr, K. U. Travers, A. Gueye-Ndiaye, S. Mboup, M. E. Essex, and P. J. Kanki. 1999. Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2. J. Infect. Dis. 180:1116-1121. [PubMed]
33. Poulsen, A. G., P. Aaby, O. Larsen, H. Jensen, A. Naucler, I. M. Lisse, C. B. Christiansen, F. Dias, and M. Melbye. 1997. 9-year HIV-2-associated mortality in an urban community in Bissau, west Africa. Lancet 349:911-914. [PubMed]
34. Reynes, J., P. Portales, M. Segondy, V. Baillat, P. Andre, O. Avinens, M. C. Picot, J. Clot, J. F. Eliaou, and P. Corbeau. 2001. CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. AIDS 15:1627-1634. [PubMed]
35. Ribeiro, R. M., M. D. Hazenberg, A. S. Perelson, and M. P. Davenport. 2006. Naive and memory cell turnover as drivers of CCR5-to-CXCR4 tropism switch in human immunodeficiency virus type 1: implications for therapy. J. Virol. 80:802-809. [PMC free article] [PubMed]
36. Schnittman, S. M., H. C. Lane, J. Greenhouse, J. S. Justement, M. Baseler, and A. S. Fauci. 1990. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc. Natl. Acad. Sci. USA 87:6058-6062. [PMC free article] [PubMed]
37. Schramm, B., M. L. Penn, E. H. Palacios, R. M. Grant, F. Kirchhoff, and M. A. Goldsmith. 2000. Cytopathicity of human immunodeficiency virus type 2 (HIV-2) in human lymphoid tissue is coreceptor dependent and comparable to that of HIV-1. J. Virol. 74:9594-9600. [PMC free article] [PubMed]
38. Shea, A., D. A. Sarr, N. Jones, L. Penning, G. Eisen, A. Gueye-Ndiaye, S. Mboup, P. Kanki, and H. Cao. 2004. CCR5 receptor expression is down-regulated in HIV type 2 infection: implication for viral control and protection. AIDS Res. Hum. Retrovir. 20:630-635. [PubMed]
39. Shi, Y., E. Brandin, E. Vincic, M. Jansson, A. Blaxhult, K. Gyllensten, L. Moberg, C. Brostrom, E. M. Fenyo, and J. Albert. 2005. Evolution of human immunodeficiency virus type 2 coreceptor usage, autologous neutralization, envelope sequence and glycosylation. J. Gen. Virol. 86:3385-3396. [PubMed]
40. Sol, N., F. Ferchal, J. Braun, O. Pleskoff, C. Treboute, I. Ansart, and M. Alizon. 1997. Usage of the coreceptors CCR-5, CCR-3, and CXCR-4 by primary and cell line-adapted human immunodeficiency virus type 2. J. Virol. 71:8237-8244. [PMC free article] [PubMed]
41. Soriano, V., P. Gomes, W. Heneine, A. Holguin, M. Doruana, R. Antunes, K. Mansinho, W. M. Switzer, C. Araujo, V. Shanmugam, H. Lourenco, J. Gonzalez-Lahoz, and F. Antunes. 2000. Human immunodeficiency virus type 2 (HIV-2) in Portugal: clinical spectrum, circulating subtypes, virus isolation, and plasma viral load. J. Med. Virol. 61:111-116. [PubMed]
42. Sousa, A. E., J. Carneiro, M. Meier-Schellersheim, Z. Grossman, and R. M. Victorino. 2002. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J. Immunol. 169:3400-3406. [PubMed]
43. Sousa, A. E., A. F. Chaves, A. Loureiro, and R. M. Victorino. 2001. Comparison of the frequency of interleukin (IL)-2-, interferon-gamma-, and IL-4-producing T cells in 2 diseases, human immunodeficiency virus types 1 and 2, with distinct clinical outcomes. J. Infect. Dis. 184:552-559. [PubMed]
44. Venkatesan, S., A. Petrovic, D. I. Van Ryk, M. Locati, D. Weissman, and P. M. Murphy. 2002. Reduced cell surface expression of CCR5 in CCR5Delta 32 heterozygotes is mediated by gene dosage, rather than by receptor sequestration. J. Biol. Chem. 277:2287-2301. [PubMed]
45. Whittle, H., J. Morris, J. Todd, T. Corrah, S. Sabally, J. Bangali, P. T. Ngom, M. Rolfe, and A. Wilkins. 1994. HIV-2-infected patients survive longer than HIV-1-infected patients. AIDS 8:1617-1620. [PubMed]

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