HIV in women of child- bearing age is increasing; 10-40% may transmit infection to their infants. Yet, factors that may prevent maternal transmission have not been defined, nor have early diagnostic techniques been optimized. The goals are: 1) to characterize protective cellular immune responses in relation to virologic parameters in HIV-infected mothers to more effectively design immunotherapy to interrupt maternal transmission, and 2) to define cellular immunity to HIV in relation to viral load in at-risk infants for the early identification and timing of HIV infection. The hypothesis is that HIV-specific maternal cellular immune mechanisms are protective for infants by controlling viral replication, thereby limiting viral burden. Perinatal exposure to HIV will induce specific cellular immune responses in infants that can be used in conjunction with virologic parameters for early diagnosis of infection.
The specific aims for the prospective maternal studies are: to assess specific anti-HIV cellular immune function utilizing assays for CD8 T cell mediated suppression of HIV replication and CD4 T cell generation of IL-2 in response to HIV peptides; characterize cellular -immune activation by activation antigen expression on CD8 cells and beta2-microglobulin and neopterin in serum; quantitate viral load and biologically clone maternal isolates by limiting dilution cell co- culture; assess the ability of antibody from HIV-infected pregnant women to neutralize autologous viral isolates as compared to isolates from their infected infants to assess viral escape variants; characterize selected maternal viral isolates biologically for cell tropism and molecularly by PCR and amino acid sequence of conserved regions within the V3 loop of gp120.
The specific aims i n the neonatal studies are: to characterize the early cellular immune response to HIV utilizing the CD4 T cell functional assay described above; characterize early cellular immune activation as reflected in the expression of CD4, CD8 cells, and monocyte activation/differentiation antigens and beta2-microglobulin and neopterin in serum; determine the ability of CD4 cells from at-risk infants to produce HIV in a unique enhanced culture system; characterize viral isolates biologically and molecularly for cell tropism vis a vis maternal isolates. About 110 pregnant HIV-infected women will be enrolled early in pregnancy and followed prospectively every 3 months prenatally, and for 6 months postpartum. Infants will be followed from birth to 8 weeks for early diagnosis studies, then for 24 months or until diagnosis of infection. The experimental design will include the correlation of the innovative immunologic and virologic techniques described above. These studies will provide essential information in HIV-infected mothers and infants that will allow therapeutic intervention to decrease maternal transmission and infant morbidity.
| Ahmed, Simi T; Darnell Jr, James E (2009) Serpin B3/B4, activated by STAT3, promote survival of squamous carcinoma cells. Biochem Biophys Res Commun 378:821-5 |
