Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: Comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo

Cell surface receptors exploited by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for infection are major determinants of tropism. HIV-1 usually requires two receptors to infect cells. Gp120 on HI V-1 virions binds CD4 on the cell surface, triggering conformational rearra ngements that create or expose a binding site for a seven-transmembrane (7T M) coreceptor. Although HIV-2 and SIV strains also use CD4, several laborat ory-adapted HIV-2 strains infect cells without CD4, via an interaction with the coreceptor CXCR4. Moreover, the envelope glycoproteins of SIV of macaq ues (SIVMAC) can bind to and initiate infection of CD4(-) cells via CCR5. H ere, we show that most primary HIV-2 isolates can infect either CCR5(+) or CXCR4(+) cells without CD4. The efficiency of CD4-independent infection by HIV-2 was comparable to that of SIV, but markedly higher than that of HIV-1 . CD4(-)independent HIV-2 strains that could use both CCR5 and CXCR4 to inf ect CD4(+) cells were only able to use one of these receptors in the absenc e of CD4. Our observations therefore indicate (i) that HIV-2 and SIV envelo pe glycoproteins form a distinct conformation that enables contact with a 7 TM receptor without CD4, and (ii) the use of CD4 enables a wider range of 7 TM receptors to be exploited for infection and may assist adaptation or swi tching to new coreceptors in vivo. Primary CD4(-) fetal astrocyte cultures expressed CXCR4 and supported replication by the T-cell-line-adapted ROD/B strain. Productive infection by primary X4 strains was only triggered upon treatment of virus with soluble CD4. Thus, many primary HIV-2 strains infec t CCR5(+) or CXCR4(+) cell lines without CD4 in vitro. CD4(-) cells that ex press these coreceptors in vivo, however, may still resist HIV-2 entry due to insufficient coreceptor concentration on the cell surface to trigger fus ion or their expression in a conformation nonfunctional as a coreceptor. Ou r study, however, emphasizes that primary HIV-2 strains carry the potential to infect CD4(-) cells expressing CCR5 or CXCR4 in vivo.