Abstract
Unusual HIV-1 nef alleles were isolated from a woman and her vertically infected child. Both patients eventually progressed to develop AIDS. The child died at age 6.5 years, while the mother is currently alive, 13 years since her diagnosis with HIV-1. Predicted amino acid sequences of both mother and child Nefs diverged from the HIV-1 clade B consensus. In particular, they exhibited two separate 5-amino acid deletions bracketing a Cterminal dileucine regulatory motif and Trp-Gly mutations at the site for cleavage by the HIV-1 protease. The child’s Nef showed a modest ability to enhance HIV-1 infectivity in MAGI cells, whereas the mother’s Nef did not alter HIV-1 infectivity in the assay. Both Nefs were partially functional for CD4 down-regulation. The child’s Nef was fully functional for MHC-1 down-regulation, while the maternal Nef was non-functional. To our knowledge this study is the first to describe a functional divergence between Nef alleles in a case of mother-to-child HIV-1 transmission.
Highlights
The nef genes of human immunodeficiency (HIV-1) and simian immunodeficiency (SIV) viruses encode 27-34 kd myristoylated proteins, which are expressed early after establishment of the provirus in host cells [1]
Isolation of nef alleles The polymerase chain reaction (PCR) amplification of the HIV-1 nef gene from proviral DNA samples from both mother (M29) and child (C28B), yielded amplicons that were visibly shorter than standard nef amplicons
The presence of the dileucine motif in an unusual context, together with additional mutations in the amino acid sequences of both patient Nefs led us to examine whether their activities might be altered in various assays of Nef function, including viral infectivity and down-regulation of cell surface CD4 and major histocompatibility class I (MHC-I) antigens
Summary
The nef genes of human immunodeficiency (HIV-1) and simian immunodeficiency (SIV) viruses encode 27-34 kd myristoylated proteins, which are expressed early after establishment of the provirus in host cells [1]. A number of LTS individuals remained healthy more than 10 years after a diagnosis of HIV-1 infection in the absence of ongoing antiretroviral therapy [9]. For many of these patients, the lack of expression of Nef was the only observable attenuation of the HIV-1 virus. It was demonstrated in transgenic mouse models for HIV1 infection that expression of the HIV-1 nef gene increases cytotoxic and pathogenic effects [11,12]
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