Background:  CC chemokine ligand 3-like (CCL3-L1) is one of the functional genes responsible for production of the CCR5 ligand CCL3. CCL3-L1 genes occur in variable copy numbers among individuals and across populations. Individuals with higher numbers of CCL3-L1 copies relative to their population have been found to be at lower risk of HIV transmission and disease progression. We tested whether infant’s and mother’s CCL3-L1 gene copy numbers were associated with perinatal HIV infection in the context of nevirapine (NVP) given to prevent transmission.

Method:   We followed prospectively 852 HIV-infected mother-infant pairs at 2 hospitals in Johannesburg, South Africa, as part of 4 cohorts; 83 infants were infected (transmission rate 10%). Some mothers (n = 574) received single-dose NVP for prevention of perinatal transmission as part of routine services. Other mothers (n = 209), who had not accessed testing antenatally, were identified post-partum and their infants received post-exposure prophylaxis. The remainder received other ART interventions. DNA samples were sought from all mothers and infants of transmitting pairs and a random sample 2:1 of non-transmitting pairs. CCL3-L1 gene copy number per diploid genome was determined by real-time polymerase chain reaction with β-globin and CCL3 as controls.

Results:  Overall infant, but not maternal, CCL3-L1 gene copies were associated with transmission:  higher CCL3-L1 copies were more frequent among uninfected vs infected infants (34% vs 22% with >5 copies per diploid genome) whereas lower CCL3-L1 copies were less frequent among uninfected vs infected infants (18% vs 33% with <4 copies per diploid genome) (p = 0.005). The association was confined to infants whose mothers had not received single-dose NVP:  median CCL3-L1 copies 4 vs 5 per diploid genome among infected vs uninfected infants, respectively (p = 0.03). No trend in support of this association was apparent among infants whose mothers were exposed to single-dose NVP. Within a sub-set, we measured CCL3 production in cord blood (infant) mononuclear cells. Spontaneously-released CCL3 (p=0.005) and PHA-stimulated CCL3 (p = 0.01) was reduced among infants with (n = 37) vs without maternal NVP exposure (n = 25) (p = 0.005).  

Conclusions:  Our data support an association between higher CCL3-L1 copies and protection against HIV transmission only in the absence of maternal NVP exposure.  NVP may have anti-viral or immunomodulatory effects that partially change the role of CCR5 and its ligands in HIV transmission.