African infants CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine prophylaxis

2 October 2007. Related: Pregnancy.

Polly Clayden, HIV i-Base

People with above the population median number of copies of CC chemokine ligand 3-like1 gene number (CCL3L1, also called MIP-1-alphaP) have been found to be less susceptible to HIV acquisition. [1]

In newborn infants reduced ability to produce CCL3 is associated with increased susceptibility to mother to child transmission (MTCT) of HIV. [2]

A paper authored by Louise Kuhn coworkers from Johannesburg and Soweto, South Africa and Columbia University, New York, USA reported findings from a study to investigate whether infants’ and mothers’ CCL3L1 gene copy numbers are associated with perinatal transmission. The investigators looked at infants born to mothers both receiving and not receiving singe dose nevirapine for MTCT prophylaxis. [3]

This was a nested case-control study in which data was combined from four cohorts. This included 849 HIV-positive mothers and their infants followed prospectively at two hospitals in Johannesburg, South Africa. The study compared HIV-positive mothers with HIV-positive infants (transmitting cases) to HIV-positive mothers with HIVnegative infants (non-transmitting controls).

The transmission rate across the cohorts was approximately 10%; 83 infants were HIV-positive. The CCL3L1 gene copy number was determined by real-time polymerase chain reaction (PCR) for mothers and infants from 79/83 transmitting pairs.

235 non-transmitting pairs matched by cohort were randomly selected as controls. The use of antiretroviral drugs for MTCT prophylaxis varied across the cohorts (totals shown Table 1).

Table 1: Use of maternal MTCT prophylaxis. In parenthesis are the numbers of pairs with genotype data available

The transmission rate among infants whose mothers received single-dose nevirapine was 8.5% (49/576). The rate among infants who received postexposure prophylaxis and whose mothers received no antiretroviral drugs was 11.9% (24/201) and among infants whose mothers received triple combination therapy was 4.9% (2/41).

Unsurprisingly, of the case controls, mothers that transmitted had higher viral loads (median 58,100 [IQR 5820-219,00] vs. 13,100 [IQR 1,950-55,400] copies/mL, p<0.0001) and lower CD4 counts (416 [std 223] vs 502 [std 264] cellsmm3, p=0.01) than non-transmitting mothers.

The investigators found that infant, but not maternal, CCL3L1 gene copies were significantly associated with perinatal HIV transmission (p=0.004).

After adjustment for maternal CCL3L1 copies, viral load, and CD4 cell count, there continued to be a significant association between higher numbers of infant CCL3L1 gene copies (continuous scale) and a lower risk of HIV transmission (OR 0.75, 95% CI 0.59–0.95, p=0.018).

The influence of infant CCL3L1 copies on transmission was attenuated if mothers received single-dose nevirapine or had low viral loads (irrespective of maternal drug regimens).

Additionally the investigators found that spontaneously released CCL3 (p=0.007) and phytohemagglutinin-stimulated CCL3 (p=0.005) was reduced for HIV-exposed, HIV-negative infants whose mothers took nevirapine, compared to those whose mothers took no antiretrovirals.

The investigators acknowledge that a limitation of this study is that they only investigated nevirapine. It is unclear whether similar attenuations of genotype transmission would be observed with other antiretroviral drugs.

In the discussion they wrote: “Our results have important implications for future studies of mother-to-child HIV transmission. First, for ethical reasons, it is unlikely in the future to find contexts in which vertical transmission can be studied in the absence of antiretroviral drugs. It appears, however, that some antiretroviral drugs currently used for prevention may obscure genotype–transmission relationships.”

They added: “Second, a vaccine to prevent breastfeeding HIV transmission would be extremely beneficial for settings in which avoiding all breastfeeding is neither safe nor acceptable. It is likely that studies of infant vaccines will include antiretroviral drugs given at least over the perinatal period. If these drugs influence CCL3 production they may affect the immunogenicity of vaccines that rely on appropriate support from this component of innate immunity. For these reasons, it is important that the indirect consequences of antiretroviral drugs used for the prevention of perinatal HIV transmission be investigated further.”

References:

1. Townson JR, Barcellos LF, Nibbs RJ. Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 2002; 32:3016–3026.
2. Meddows-Taylor S, Donninger SL, Paximadis M et al. Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission. J Gen Virol 2006; 87:2055–2065.
3. Kuhn L , Schramm D B, Donninger S et al. African infants’ CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine. AIDS 2007, 21:1753–1761.