Abstract
Individuals who exhibit long-term HIV suppression and CD4 T-cell preservation without antiretroviral therapy are of great interest for HIV research. There is currently no robust method for rapid identification of these “HIV controller” subjects; however, HLA-B*57 (human leukocyte antigen (major histocompatibility complex), class I, B*57) genotype exhibits modest sensitivity for this phenotype. Complement C3b and C4b can influence HIV infection and replication, but studies have not examined their possible link to HIV controller status. We analyzed HLA-B*57 genotype and complement levels in HIV-positive patients receiving suppressive antiretroviral therapy, untreated HIV controllers, and HIV-negative subjects to identify factors associated with HIV controller status. Our results revealed that the plasma levels of three C4b-derived peptides and complement factor I outperformed all other assayed biomarkers for HIV controller identification, although we could not analyze the predictive value of biomarker combinations with the current sample size. We believe this rapid screening approach may prove useful for improved identification of HIV controllers.
Highlights
A small fraction of HIV-infected individuals exhibit longterm viral control and CD4 T-cell preservation in the absence of antiretroviral therapy.[1,2]. These “HIV controllers” can be divided into viremic controllers (VCs; ∼3.34% of HIVpositive patients), who have low but detectable viremia, and rare elite controllers (ECs; ∼0.55%), who have undetectable viremia by conventional assays.[2−7] Recent work has shown that ECs harbor replicationcompetent viruses, strongly suggesting that host factors rather than defective viral infections contribute to HIV suppression.[2,10,8]
complement receptor 1 (CR1) interacts with complement factor I (CFI), which plays a critical role in complement cascades by cleaving and inactivating C3b and C4b,23,24 including HIV-bound C3b,25 suggesting that CFI may attenuate HIV pathogenesis by inactivating HIV-conjugated C3b and C4b (Figure 1)
There were no significant differences in age or sex distribution among these populations, the HN subject group tended to be younger and have fewer males
Summary
To evaluate parameters specific to our EC cohort, we enrolled three reference groups: (1) viremic controllers (VC), (2). Consistent with previously reported data,[26] plasma levels of complement C3 and C4 did not differ among the patient groups (Figure 2B,C), but MS analysis of nanotrap-enriched peptides identified three predicted C4b fragments (m/z 1626.88, 1739.94, and 1896.04) associated with CFI activity[27] that were higher in EC than AT and HN subjects (Figure 2D).
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