AEGiS-12IAC: Positive selection of Vpr in human immunodeficiency virus type 1 infection and disease progression.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

Positive selection of Vpr in human immunodeficiency virus type 1 infection and disease progression.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:11 (abstract no. 11147)

Saksena N, Wang B, Joswiak R
Retroviral Genetics Lab, Westmead Hospital WIHR CVR, NSW, Australia.

OBJECTIVES: 1. To study the role of defects in the Vpr gene in long-term non-progression of HIV disease 2. To determine the role of repair of defects and the positive selection of the Vpr gene in HIV disease progression

DESIGN: Long-term non-progression of HIV disease was studied for the Vpr gene evolution and repair directly from the PBMCs and plasma of a mother and child pair which has survived for 15 years with high CD4 T-cell counts since 1983. Mother acquired the virus through blood transfusion, whereas the child acquired HIV-1 via breast feeding.

METHODS: Peripheral blood cells and plasma were collected from from both mother and child from 1987-1997. Proviral sequences were amplified in the Vpr gene from both plasma and PBMCs, and cloning was performed in PGEM-T vector. Multiple clones were sequenced from each time point. Co-culture studies were carried out on PBMCs and monocyte-derived macrophages for deriving information on replication kinetics and tropism of HIV-1 strains infecting the mother-child pair.

RESULTS: Molecular analyses of both plasma and PBMC-derived clones from 1987-1996 clearly revealed that overall 77% of the Vpr gene clones carried defects (deletions/insertions) at the C-terminus of the vpr protein which affected the size of the vpr gene, and also the frame of tat protein. Between 1987-1996, both mother and child maintained high CD4 counts (750-800/uL blood), but in 1997 both started showing decline in their CD4 counts (400-450/uL, blood). Interestingly, the sequencing of the Vpr gene from the PBMCs obtained in 1997 showed no defects at the C-terminus. We propose that the repair of the defects at the C-terminus may have crucial role in HIV disease progression in these individuals. In addition, it is known that the defective Vpr can lead to persistent infection in T-cells, whereas an intact Vpr can cause cell-cycle arrest which may lead to disease progression. Defects at the C-terminus are important because they are known to downregulate the cell cycle arrest.

CONCLUSIONS: These are the first studies showing sequentially that the positive selection of the Vpr may have an important role in HIV disease progression. Our data may have important implications in the designing of therapeutics for HIV treatment.

Keywords: AEGIS, HIV-1, Disease Progression, Gene Products, vpr, Genes, vpr, HIV Infections, Virus Replication, HIV-2, Acquired Immunodeficiency Syndrome, CD4 Lymphocyte Count, Selection (Genetics), Gene Products, tat, T-Lymphocytes, Greece, Child, Human, genetics, virology, ICA12
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