Autocrine Production of β-Chemokines Protects CMV-Specific CD4+ T Cells from HIV Infection

Abstract

Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1α and MIP-1β mRNA, resulting in a rapid increase in production of MIP-1α and MIP-1β after cognate antigen stimulation. Production of β-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of β-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1β contained 10 times less Gag DNA than did those which failed to produce MIP-1β. These data suggest that CD4+ T cells which produce MIP-1α and MIP-1β bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.

Memory CCR6+CD4+ T Cells Are Preferential Targets for Productive HIV Type 1 Infection Regardless of Their Expression of Integrin β7

“…Levels of RARa mRNA were similar in CCR6 however, the increase in HIV replication and viral DNA integration was insignificant. Of note, ATRA did not interfere with the production of CCL3, a CCR5-binding chemokine demonstrated to play a role in protecting cells from infection in an autocrine manner (8). Thus, increased HIV replication in ATRAtreated CCR6 + T cells cannot be linked to a decreased protection against CCR5-mediated HIV entry.…”

“…This might be why CMVspecific responses are relatively well conserved in HIV-infected individuals. These differences are explained, at least in part, by differences in HIV coreceptor CCR5 expression (6,7) and the autocrine production of CCR5 binding chemokines (CCL3, CCL4) (8). Molecular mechanisms controlling distinct transcriptional programs in HIV-and CMV-specific T cells remain unknown, but they are likely related to specific differentiation/ activation signals present in the anatomic sites where T cell priming takes place, such as the GALTs for HIV-specific T cells.…”

Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals

“…We and several other groups have shown that human CD4 T cells specific to different antigens, such as HIV (26,27), CMV (8,28), tetanus toxoid, and Candida albicans (8), can be protected from HIV by autocrine production of β-chemokines. The microarray analysis in our study (Fig.…”

Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of β chemokines and RNases

“…This is underscored by their higher expression levels in primary PHA-activated T cells from HIV + asymptomatic compared with HIV + symptomatic individuals. The enhanced replication of X4 HIV strains by neutralization of the endogenous β chemokines I-309, MDC, and TARC suggests a protective role for these chemokines against infection of CD4 + T cells by X4 viruses, as has previously been described for the antiviral CCR5 ligands that can protect HIV-antigen specific CD4 + T cells against R5 viruses (15)(16)(17)(18). A number of posttranslational modifications, including NH 2 -and COOH-terminal proteolytic processing and glycosylation, have been described for natural chemokines, with a variety of consequences for their biological activity (28).…”

“…Our group identified the β chemokines, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated-on-activation normal T-cell expressed and secreted (RANTES), as major mediators of the CD8 suppressive activity against R5 HIV-1 isolates (8) that depend upon CC chemokine receptor (CCR)5 for entry (9), and, later, we and others showed that levels of some correlated with protection against infection, as well as with an asymptomatic clinical status in HIV infection (10)(11)(12)(13)(14). Our group and others also reported that CD4 + T cells secreting antiviral CCR5 ligands are self-protected against infection with R5 virus during the primary immune response in vitro (15)(16)(17)(18). Therefore, it is clear that the suppressive soluble anti-HIV R5 factors are a collection of β chemokines, which are derived from both CD4 + and CD8 + cells.…”