Sensitivity to inhibition by β-chemokines correlates with biological phenotypes of primary HIV-1 isolates

Abstract

Primary HIV-1 isolates were evaluated for their sensitivity to inhibition by ␤-chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1␣ (MIP-1␣), and MIP-1␤. Virus isolates of both nonsyncytium-inducing (NSI) and syncytium-inducing (SI) biological phenotypes recovered from patients at various stages of HIV-1 infection were assessed, and the results indicated that only the isolates with the NSI phenotype were substantially inhibited by the ␤-chemokines. More important to note, these data demonstrate that resistance to inhibition by ␤-chemokines RANTES, MIP-1␣, and MIP-1␤ is not restricted to T cell line-adapted SI isolates but is also a consistent property among primary SI isolates. Analysis of isolates obtained sequentially from infected individuals in whom viruses shifted from NSI to SI phenotype during clinical progression exhibited a parallel loss of sensitivity to ␤-chemokines. Loss of virus sensitivity to inhibition by ␤-chemokines RANTES, MIP-1␣, and MIP-1␤ was furthermore associated with changes in the third variable (V3) region amino acid residues previously described to correlate with a shift of virus phenotype from NSI to SI. Of interest, an intermediate V3 genotype correlated with a partial inhibition by the ␤-chemokines. In addition, we also identified viruses sensitive to RANTES, MIP-1␣, and MIP-1␤ of NSI phenotype that were isolated from individuals with AIDS manifestations, indicating that loss of sensitivity to ␤-chemokine inhibition and shift in viral phenotype are not necessarily prerequisites for the pathogenesis of HIV-1 infection.

Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

“…26 In contrast, other investigations of longitudinally followed HIV-1-infected subjects demonstrate that sensitivity to coreceptor and fusion antagonists decreases from the chronic to the late phase of disease. [22][23][24][25] One of the major differences with our study and these previous publications is that we examined variants from the early and chronic phase of infection in a highly characterized seroincident cohort with well-defined dates of estimated seroconversion as opposed to comparing variants from the chronic and late stage of disease. In addition, we observed no significant differences in both PBMC-passaged and 293T-derived nonpassaged recombinant viruses, suggesting that sensitivity changes to CCR5 and fusion blockers were not an artifact from in vitro selection.…”

“…In addition to receptor usage changes, HIV-1's sensitivity to various antiretroviral drugs changes over time. We and others have shown that over the course of infection, envelopes have decreased sensitivity to CCR5 receptor and fusion inhibitors, [21][22][23][24][25] although this has not been a universal observation in all subjects. 26 Given the extensive changes observed in both the envelope and polymerase gene, it remains unclear if the sensitivity changes are observed only for entry blockers or also against other drugs from different antiretroviral classes.…”

Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8+T cells are associated with asymptomatic HIV-1 infection

“…independent of the sensitivity of their primary isolates to the antiviral effect of the recombinant ␤ chemokine in vitro (54,55), might instead reflect a decreased ability of the CD8 ϩ T cells to produce the antiviral ␤-chemokine MIP-1␣ and MIP-1␤.…”

“…HIV-1 disease progression is not necessarily associated with virus insensitivity to the ␤-chemokine effect (54,55), because 50% of the HIV-1 ϩ subjects who developed AIDS harbor nonsyncytia inducing viruses (56). The loss of viral control in these patients, Fig.…”

Do beta-chemokines have clinical relevance in HIV infection?

“…First, regulated upon activation of normal T cell expressed and secreted (RANTES), 1 macrophage inflammatory protein-1 ␣ (MIP-1 ␣ ), and macrophage inflammatory protein-1 ␤ (MIP-1 ␤ ), members of the ␤ -chemokine family, were demonstrated to be potent inhibitors of HIV replication in vitro (9), although not all virus strains have been found to be sensitive to this antiviral activity (9)(10)(11). Second, the chemokine receptors CCR5 and CXCR4 (fusin) were shown to be efficient coreceptors for macrophage-tropic and T cell line-tropic strains of HIV, respectively (12)(13)(14)(15)(16)(17).…”