Abstract
Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.
Highlights
It is well established that some persons who have been exposed to HIV-1 repeatedly, or who exhibit behaviors associated with a high risk of infection, can remain uninfected [1,2,3,4]
The top 40 HIV-exposed seronegatives (HESN) had a median of 73 partners, while the top 40 low exposure HIV-1 seroconverters (LESC) had a median of 2 partners in the 2.5 years prior to sampling
We found weak trends between HESN status and lower CD4+ T-cell counts (MannWhitney U test, P = 0.13; HESN median = 899 cells/uL; LESC median = 1116) (S1 Fig.) and CD8+ T-cell counts
Summary
It is well established that some persons who have been exposed to HIV-1 repeatedly, or who exhibit behaviors associated with a high risk of infection, can remain uninfected [1,2,3,4]. These individuals have been referred to as HIV-exposed seronegatives (HESN) [1], and PLOS ONE | DOI:10.1371/journal.pone.0119218. The only host genetic factor consistently found to be associated with protection from HIV infection is a homozygous 32 base pair deletion in the CCR5 gene, which encodes a major viral coreceptor [5,6,7]. Additional candidates suggested to affect host susceptibility to HIV-1 infection include TRIM5α [13,14], specific KIR-HLA associations [15], APOBEC3G [16,17], TAP2 Ala665 [18], IRF1 [19], DC-SIGN [20], and TLR9 [21]
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