Importance of the state of activation and/or differentiation of CD4+ T cells in AIDS pathogenesis

Response from Veazey et al.We are encouraged by the comments of Stefano Fais in response to our recent Review [1xThe mucosal immune system: primary target for HIV infection and AIDS. Veazey, R.S. et al. Trends Immunol. 2001; 22: 626–633Abstract | Full Text | Full Text PDF | PubMed | Scopus (99)See all References[1] and apologize for our oversight in not citing the papers that he mentions, which support our hypothesis clearly [2xHuman intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Lapenta, C. et al. Eur. J. Immunol. 1999; 29: 1202–1208Crossref | PubMedSee all References, 3xHuman lymphoblastoid CD4(+) T cells become permissive to macrophage-tropic strains of human immunodeficiency virus type 1 after passage into severe combined immunodeficient mice through in vivo up-regulation of CCR5: in vivo dynamics of CD4(+) T-cell differentiation in pathogenesis of AIDS. Lapenta, C. et al. J. Virol. 1998; 72: 10323–10327PubMedSee all References]. It is increasingly apparent from studies by Fais et al., Anton et al. and others that human intestinal CD4+ T cells are the major early target of HIV-1 infection, owing apparently to their state of activation and expression of specific chemokine receptors [2xHuman intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Lapenta, C. et al. Eur. J. Immunol. 1999; 29: 1202–1208Crossref | PubMedSee all References, 3xHuman lymphoblastoid CD4(+) T cells become permissive to macrophage-tropic strains of human immunodeficiency virus type 1 after passage into severe combined immunodeficient mice through in vivo up-regulation of CCR5: in vivo dynamics of CD4(+) T-cell differentiation in pathogenesis of AIDS. Lapenta, C. et al. J. Virol. 1998; 72: 10323–10327PubMedSee all References, 4xHuman immunodeficiency virus type 1 strains R5 and X4 induce different pathogenic effects in hu-PBL-SCID mice, depending on the state of activation/differentiation of human target cells at the time of primary infection. Fais, S. et al. J. Virol. 1999; 73: 6453–6459PubMedSee all References, 5xEnhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. Anton, P.A. et al. AIDS. 2000; 14: 1761–1765Crossref | PubMed | Scopus (116)See all References, 6xA preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. Poles, M.A. et al. J. Virol. 2001; 75: 8390–8399Crossref | PubMed | Scopus (104)See all References, 7xMucosal HIV infection. Ullrich, R. et al. Pathobiology. 1998; 66: 145–150Crossref | PubMed | Scopus (24)See all References, 8xLoss of mucosal CD4 lymphocytes is an early feature of HIV infection. Lim, S.G. et al. Clin. Exp. Immunol. 1993; 92: 448–454Crossref | PubMedSee all References].Moreover, the findings of Fais et al. in prospective studies – demonstrating that an immunological shift from naive to memory CD4? T cells occurs in severe combined immunodeficient (SCID) mice following the transplantation of human peripheral-blood lymphocytes – are intriguing and demonstrate further the importance of prospective studies using animal models of HIV-1 infection. These studies raise an important issue regarding the interpretation of prospective studies, compared with retrospective or cross-sectional studies. It is difficult to perform prospective immunological studies of the intestinal tract in humans; therefore, the SIV macaque model and human SCID models of HIV-1 infection are invaluable for examining immunological events that might occur in individuals over the course of an infection, particularly during primary infection. Cross-sectional studies of humans might provide useful information, but must be interpreted with caution because they provide only a single picture of a dynamic process. For example, a cross-sectional comparison of HIV-1-infected and uninfected patients might reveal no differences in the state of cellular activation in the intestine, simply because the dynamics of CD4+ T-cell destruction and turnover are not considered fully. This might, at least partially, explain the results of studies that have failed to demonstrate an increase in the level of expression of cellular activation markers in human intestinal tissues of chronically HIV-1-infected patients, despite a demonstrated increase in intestinal T-cell proliferation [9xLack of evidence for small intestinal mucosal T-cell activation as a pathogenic mechanism in African HIV-associated enteropathy. Veitch, A.M. et al. Dig. Dis. Sci. 2001; 46: 1133–1138Crossref | PubMed | Scopus (3)See all References, 10xEffect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. Talal, A.H. et al. J. Acquired Immune Defic. Syndr. 2001; 26: 208–217PubMedSee all References].