Restriction of HIV-1 infection in sickle cell trait

Abstract

Patients with Sickle cell disease (SCD) have lower risk for HIV-1 infection. We showed restriction of ex vivo HIV-1 infection in SCD peripheral blood mononuclear cells (PBMCs) that was due, in part, to the upregulation of antiviral, inflammatory and hemolytic factors including heme oxygenase-1 (HO-1). Here, we investigated whether individuals with sickle cell trait (SCT), who develop mild hemolysis, also restrict HIV-1 infection. Ex vivo infection of SCT PBMCs demonstrated ~2-fold reduction of HIV-1 replication and lower levels of HIV-1 reverse transcription products, 2-Long Terminal Repeats (LTR) circles, HIV-1 integration and gag RNA expression. SCT PBMCs had higher HO-1 mRNA and protein levels and reduced ribonucleotide reductase 2 (RNR2) protein levels. HO-1 inhibition by tin porphyrin eliminated ex vivo HIV-1 restriction. Among Howard University clinic recruits, higher levels of HO-1 and RNR2 mRNA and lower HIV-1 env mRNA levels were found in SCT individuals living with HIV-1. To determine the population level effect of SCT on HIV-1 prevalence, we assessed SCT trait among women living with HIV (WLH) in the Women Interagency HIV-1 Study (WIHS). Among WIHS African American participants, prevalence of SCT was lower among women with HIV compared with uninfected women (8.7% vs 14.2%; OR 0.57; 95%CI = 0.36-0.92, p=0.020). WIHS WLH with SCT had higher levels of CD4+/CD8+ ratios over 20 years of follow up (p=0.003) than matched WLH without SCT. Together, our findings suggest that HIV-1 restriction factors including HO-1 and RNR2 might restrict HIV-1 infection among individuals with SCT and limit the pathogenicity of HIV.

Does Sickle Cell Disease Protect against HIV Infection: A Systematic Review

“…There was no publication bias (Egger's t value = 1.9902; p = 0.2964) shown in Figure 3 . In the current review, the mechanisms implicated in the protection of SCD against HIV include autosplenectomy [ 20 ], enhanced immunological defense [ 12 , 36 , 37 ], and ferroportin as a trigger of HIV-1 restriction [ 22 ] as shown in online supplementary Table 2 .…”

“…Micro-infarction is the primary cause of functional asplenia in about 95% of people with HbSS [ 21 ]. Heme and iron regulation mechanisms in SCD, as well as mild hemolysis, have all been implicated in limiting HIV-1 infection [ 22 ].…”