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

Abstract

A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 ϩ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 ϩ T cells, and individually SDF-1␤, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1␤, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 ϩ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4 ϩ T cells, the target cells for HIV infection. Furthermore, these five EC-

Influence of sickle cell disease on susceptibility to HIV infection

“…Infection and virus culture assay. As described previously, PBMCs were depleted of CD8 + T cells via CD8 positive selection kits (Stem Cell Technologies) and infected with CXCR4 (X4)-tropic virus (NL4-3) or CCR5 (R5)-tropic virus (81-A) at a multiplicity of infection (MOI) of 10 −2 ,10 −3 , and 10 −4 for 2 hrs [11]. Following infection, cells were washed and seeded into 96-well culture dishes at 1x10 6 cell/mL in R20 with 50 IU/mL rhIL-2.…”

Interferons and beyond: Induction of antiretroviral restriction factors

“…A recent study examined the plasma levels of 87 cytokines in four groups of women: 73 elite controllers, 42 under anti‐retroviral therapy, 42 with efficient viral replication, and 48 HIV‐uninfected individuals . It was found that HIV infection is generally associated with increased levels of stromal cell‐derived factor 1 (SDF‐1)/ C‐X‐C motif chemokine ligand (CXCL)12, the ligand of the HIV‐1 coreceptor CXCR4, whereas four cytokines (CCL14, CCL21, CCL27, and XCL1) were elevated in elite controllers but not in non‐controllers or individuals on ART.…”

“…Modest increases could be confirmed by qRT‐PCR and Western blot, but no functional assays were performed to show that IFITMs are responsible for the observed antiviral effects. Although these findings suggest a protective role of some cytokines against HIV‐1 replication in vivo , further studies are required to obtain more definitive proof because the differences in plasma levels between the groups and the antiviral effects of the individual cytokines were modest …”

“…The only exception was schlafen family member 11 (SLFN11), a codon usagebased inhibitor of HIV-1 protein synthesis,98 which was expressed at significantly higher levels in elite controllers compared with untreated non-controllers and ART-suppressed individuals 97. A recent study examined the plasma levels of 87 cytokines in four groups of women: 73 elite controllers, 42 under anti-retroviral therapy, 42 with efficient viral replication, and 48 HIV-uninfected individuals 99. It was found that HIV infection is generally associated with increased levels of stromal cell-derived factor 1 (SDF-1)/ C-X-C motif chemokine ligand (CXCL)12, the ligand of the HIV-1 coreceptor CXCR4, whereas four cytokines (CCL14, CCL21, CCL27, and XCL1) were elevated in elite controllers but not in non-controllers or individuals on ART.…”

CD4 T-cell transcriptome expression reversal of the lncRNA-mRNA co-expression network in elite controllervs.normal-process HIV patients

“…In addition, we identified genes that had not been studied before, whose functions were enriched into the following processes: Virus infection, immunodeficiency, apoptosis, and cytokines. Previous studies had shown that these functions are closely related to viral replication [24–25]. For instance, GNG2 (encoding G protein subunit gamma 2) showed a strong correlation with HIV in the KEGG pathway analysis.…”