HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses

Summary and ConclusionsOur results demonstrate that CD4 T cells produce HIV-1-suppressive factors against the X4 (HIV-1 IIIB ) and R5 (HIV-1 BaL ) viruses during primary responses in vitro . These activitieswere present at equivalent levels regardless of whether the cellswere activated with SEB, TSST-1, or allogeneic MDDC. Theanti-X4 activity was caused mainly by CCL22, and the anti-R5activity was caused by the R5 ligands (CCL3, CCL4, and CCL5).This finding was confirmed by using neutralizing antibodiesagainst CC chemokines to effectively reverse the anti-HIV-1-suppressor activity obtained from antigen-stimulated cells. Wealso showed that activated CD4 T cells are the major source ofthese CC chemokines as determined by flow cytometry.The HIV-1-suppressor activity of activated CD4 T cells,during primary responses, paints a more complicated picturethan expected for the means by which CD4 T cells regulateHIV-1infection.OurdatasuggestthatifCD4 TcellsencounterHIV-1 in the right context, some of them will be protectedagainst R5 and X4 viruses. This finding suggests a complicatedoutcome of acute infection in which some HIV-1-specific CD4T cells are infected and die, whereas others are resistant toHIV-1 infection by virtue of their ability to produce anti-X4 andanti-R5 factors. A major future effort will be to determinewhenever the release of these factors, known and unknown,allows some degree of ‘‘autoprotection’’ in the CD4 T cellpopulation. It is also possible that the production of theseantiviral factors drive the generation of the CD4 T cells thatfunction as the major lymphocytic reservoir of HIV-1 (reviewedin ref. 38). Most notably, our system makes it possible to addressthese issues in the context of the primary antigen-specificresponse of human CD4 T cells. These studies identify targetsfor vaccine development to prevent either infection with HIV-1or its ability to cause rapidly progressive disease.In summary, the data presented above show that solubleHIV-suppressive factors are released during primary antigen-specific responses of CD4 T cells and suggest that such re-sponses should be considered in the design of vaccines againstHIV-1 and as a mechanism whereby the host controls infectionswith this virus.