HIV-1 use CD4 receptors to infect their primary targets, CD4+ cells, whereas CD8+ cells have a protective role against HIV-1. We recently isolated HIV-1-producing CD8+ clones from two AIDS patients. Here we show that although HIV-1 produced by CD8+ cells maintained the ability to infect CD4+ cells, these viruses were able to infect CD8+ cells independent of CD4. Evidence indicates that these viruses used CD8 as a receptor to infect CD8+ cells. First, expression of CD8 was downmodulated after infection. Second, anti-CD8 antibodies blocked viral entry and replication in CD8+ cells. Finally, resistant cells became susceptible after expression of CD8. Although these viruses used CXCR4 to enter CD4+ cells, it seems that infection of CD8+ cells was independent of CXCR4 or CCR5 co-receptors. Novel changes were observed in envelope sequences of CD8-tropic viruses. These results provide initial evidence that HIV-1 can mutate to infect CD8+ cells using CD8 as a receptor.

CD8؉ T cells display a noncytotoxic activity that suppresses transcription of human immunodeficiency virus type 1 (HIV-1) in an antigen-independent and major histocompatibility complex-unrestricted manner. To date, the precise cellular and molecular factors mediating this CD8 ؉ T-cell effector function remain unsolved. Despite evidence indicating the dependence of the activity on cell-cell contact, the possibility of a membranemediated activity that represses transcription from the viral promoter remains unexplored. We therefore investigated whether this inhibition of HIV-1 transcription might be elicited by a membrane-bound determinant. Using a CD8؉ T-cell line displaying potent noncytotoxic HIV-1 suppression activity, we have identified a membrane-localized HIV-1-suppressing activity that is concomitantly secreted as 30-to 100-nm endosomederived tetraspanin-rich vesicles known as exosomes. Purified exosomes from CD8 ؉ T-cell culture supernatant noncytotoxically suppressed CCR5-tropic (R5) and CXCR4-tropic (X4) replication of HIV-1 in vitro through a protein moiety. Similar antiviral activity was also found in exosomes isolated from two HIV-1-infected subjects. The antiviral exosomes specifically inhibited HIV-1 transcription in both acute and chronic models of infection. Our results, for the first time, indicate the existence of an antiviral membrane-bound factor consistent with the hallmarks defining noncytotoxic CD8 ؉ T-cell suppression of HIV-1.

Feeding of the infection prone preterm neonate with concentrated immunologically active ingredients in the form of colostrum may have even more significant clinical implications than in the full term infants. The scarcity of knowledge on anti-infective factors in colostrum of mothers delivering prematurely prompted us to carry out this study. Colostrum was collected and analysed from 25 mothers delivering prematurely (Study group) and 10 delivering at term (Control group). Major anti-infective factors namely IgA, IgG, IgM, lactoferrin and lysozyme were quantitated and total cell, macrophage, lymphocyte and neutrophil counts were performed. The mean concentrations of IgA, lysozyme and lactoferrin of preterm colostrum were significantly higher than in full term colostrum (p less than 0.001). IgG and IgM were found to be similar in both groups. The absolute counts of total cells, macrophages, lymphocytes and neutrophils were found to be significantly higher in the preterm colostrum as compared to the full term colostrum (p less than 0.001). Though in both the groups IgA was the predominant immunoglobulin, the mean percentage of IgA in the study group was significantly higher as compared to the control group. Degree of prematurity did not have any influence on the anti-infective protein levels in colostrum. However total cells and macrophages were significantly higher in colostrum of mothers delivering severely preterm babies.

Recent studies have demonstrated that the β-chemokines RANTES, MIP-1α, and MIP-1β suppress human immunodeficiency virus type 1 (HIV-1) replication in vitro and may play an important role in protecting exposed but uninfected individuals from HIV-1 infection. However, levels of β-chemokines in AIDS patients are comparable to and can exceed levels in nonprogressing individuals, indicating that global β-chemokine production may have little effect on HIV-1 disease progression. We sought to clarify the role of β-chemokines in nonprogressors and AIDS patients by examination of β-chemokine production and HIV-1 infection in patient T-lymphocyte clones established by herpesvirus saimiri immortalization. Both CD4+ and CD8+ clones were established, and they resembled primary T cells in their phenotypes and expression of activated T-cell markers. CD4+ T-cell clones from all patients had normal levels of mRNA-encoding CCR5, a coreceptor for non-syncytium-inducing (NSI) HIV-1. CD4+ clones from nonprogressors and CD8+ clones from AIDS patients secreted high levels of RANTES, MIP1α, and MIP-1β. In contrast, CD4+ clones from AIDS patients produced no RANTES and little or no MIP-1α or MIP-1β. The infection of CD4+clones with the NSI HIV-1 strain ADA revealed an inverse correlation to β-chemokine production; clones from nonprogressors were poorly susceptible to ADA replication, but clones from AIDS patients were highly infectable. The resistance to ADA infection in CD4+clones from nonprogressors could be partially reversed by treatment with anti-β-chemokine antibodies. These results indicate that CD4+ cells can be protected against NSI-HIV-1 infection in culture through endogenously produced factors, including β-chemokines, and that β-chemokine production by CD4+, but not CD8+, T cells may constitute one mechanism of disease-free survival for HIV-1-infected individuals.