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Background:  While most low-level viremia appears to be derived from the expression of archived virus, some low-level viremias are from active viral replication. We hypothesized that low-level viremia from individuals with continued viral replication during HAART would use the CXCR4 chemokine receptor, while expressed archived virus would use the CCR5 chemokine receptor, based on when in the course of disease that each of these types of viruses were selected (late vs early, respectively).

Methods:  A bioinformatic method based on a position-specific scoring matrix of the V3 loop of env (sensitivity 84%, specificity 96%) was used to predict co-receptor use of low-level viremia sequences obtained by endpoint dilution PCR. In addition, co-receptor use from the 1 subject with non-subtype-B (subtype-D) virus was predicted by codon charge.

Results:  From 8 subjects’ low-level viremia specimens, 45 sequences encoding the C2-V5 region of env were available for prediction of co-receptor usage; 7 of the 8 subjects also had phenotype predicted by culture in MT-2 cells prior to initiation of HAART. CXCR4 receptor use was predicted for 16 of 45 sequences. These 16 sequences came from low-level viremia of 2 subjects (2/2 sequences from 1 low-level viremia episode of 1 subject, and 14/16 from 5 low-level viremia episodes in the second subject). The remaining 27 sequences, from 6 subjects were predicted to use the CCR5 chemokine receptor. Pre–HAART MT-2 results detected syncytium-inducing (presumably X4) virus in 3 of 7 subjects including 1 of 2 subjects with CXCR4 co-receptor use by low-level viremia. The 2 subjects whose low-level viremia sequences were predicted to use the CXCR4 chemokine receptor correlated to 2 of 11 subjects predicted to have active viral replication during HAART.

Conclusions:  Viral co-receptor use by low-level viremia sequences appears to correspond with the mechanism causing the low-level viremia:  low-level viremia from subjects with viral replication during HAART predominately used the CXCR4 co-receptor, and low-level viremia from expression of archived virus used the CCR5 co-receptor. These data further support our hypothesis that these 2 distinct phenomena cause low-level viremia. Further studies of larger populations are warranted to determine whether low-level viremia co-receptor use can distinguish between ongoing viral replication vs expression of archived virus, due to differences in their clinical consequences.

Keywords: Low-level viremias; Coreceptor Usage; CCR5/CXCR4