African Infants’ CC Chemokine Ligand 3-like 1 Gene Copy Numbers Influence the Risk of Perinatal HIV Transmission Only in the Absence of Maternal Nevirapine
Louise Kuhn*1, D Schramm2, S Donninger2, S Meddows-Taylor2, A Coovadia3, G Sherman2, G Gray4, and C Tiemessen2
1Columbia Univ Mailman Sch of Publ Hlth, New York, NY, US; 2Natl Inst for Communicable Diseases, Johannesburg, South Africa; 3Coronation Hosp, Johannesburg, South Africa; and 4Baragwanath Hosp, Soweto, South Africa
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.
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.
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.