Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers

Abstract

Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4؉ T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4 ؉ T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1␣ (MIP-1␣), CCL3 and CCL3L1, were found to be upregulated. The MIP-1␣, MIP-1␤, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1␣ and/or MIP-1␤ at the protein level. The supernatant from resistant EC cells contained MIP-1␣ and MIP-1␤ and was sufficient to confer R5-tropic resistance to susceptible CD4 ؉ T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCEHIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4 ؉ T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals. In the absence of antiretroviral therapy (ART), the majority of HIV-seropositive patients have detectable viral loads (VLs) and experience a slow but inevitable decline in the number of CD4 ϩ T cells, eventually culminating in the development of AIDS. However, in rare individuals (Ͻ1% of the HIV-seropositive population), viral replication is suppressed to extremely low or undetectable levels. These patients, termed elite controllers (ECs), typically retain relatively high CD4 ϩ T cell counts and do not progress to AIDS, even in the absence of ART (1-4). Sequencing of HIV and in vitro functional assays suggest that most ECs possess replicationcompetent virus (5). Long-term nonprogressors (LTNPs), representing ϳ2 to 15% of HIV-seropositive patients, are a second group of individuals with a protective phenotype, in whom the virus continues to rep...

Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

“…CCL4 and CCL7 both bind to HIV co-receptor CCR5 with CCL4 being a known HIV-1suppressive factor (for CCR5-tropic strains) by acting as a competitor to viral binding site (24). Our finding of increased CCL4 levels in EC is consistent with a study by Walker et al (25). CCL20 was shown to have antiviral activity against HIV-1 in the female reproductive tract with a direct interaction of this chemokine with HIV-1 as the proposed mechanism of inhibition (26).…”

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression

“…The results of our study recapitulated those of Platten et al with the exception of the results for CCL4. It has been shown that a subset of ECs contain CD4 ϩ T cells that produce high levels of CCL4, rendering these cells resistant to R5 virus infection (43). In total, our identification of cytokines elevated in ECs but not in NCs or ART subjects revealed cytokines not previously associated with control of HIV infection, and our findings were largely consistent with the few prior comparative observations made in ECs.…”

Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

“…Additional important aspects of their T cell function have been reported, including low levels of T-cell activation [10], up regulation of survival factors such as bcl-2 [11], up regulation of cyclin dependent kinase inhibitors such as p21 [12] and higher frequency of expression of costimulatory molecule CD73 [13]. Furthermore, cells from EC are less susceptible to infection and effectively suppress in-vitro HIV replication [8, 14]. The EC group is also enriched for HLA-B*27 and B*57 alleles that have been associated with protection from HIV disease progression [15, 16].…”