Abstract
A small subset of human immunodeficiency virus type 1 (HIV-1)-infected, therapy-naive individuals--referred to as long-term non-progressors (LTNPs)--maintain a favourable course of infection, often being asymptomatic for many years with high CD4(+) and CD8(+) T-cell counts (>500 cells μl(-1)) and low plasma HIV-RNA levels (<10 ,000 copies ml(-1)). Research in the field has undergone considerable development in recent years and LTNPs offer a piece of the puzzle in understanding the ways that persons can naturally control HIV-1 infection. Their method of control is based on viral, genetic and immunological components. With respect to virological features, genomic sequencing has shown that some LTNPs are infected with attenuated strains of HIV-1 and harbour mutant nef, vpr, vif or rev genes that contain single nuclear polymorphisms, or less frequently, large deletions, in conserved domains. Studies have also shown that some LTNPs have unique genetic advantages, including heterozygosity for the CCR5-Δ32 polymorphism, and have been found with excitatory mutations that upregulate the production of the chemokines that competitively inhibit HIV-1 binding to CCR5 or CXCR4. Lastly, immunological factors are crucial for providing LTNPs with a natural form of control, the most important being robust HIV-specific CD4(+) and CD8(+) T-cell responses that correlate with lower viral loads. Many LTNPs carry the HLA class I B57 allele that enhances presentation of antigenic peptides on the surface of infected CD4(+) cells to cytotoxic CD8(+) T cells. For these reasons, LTNPs serve as an ideal model for HIV-1 vaccine development due to their natural control of HIV-1 infection.
Highlights
Who are long-term non-progressors?Years after the initiation of the 1981 AIDS pandemic, a small subset of human immunodeficiency virus type 1 (HIV-1)-infected individuals emerged with a markedly slow disease progression to AIDS
Choudhary et al (2005) found that in the absence of interleukin-1 (IL-1) and transforming growth factor beta (TGF-b) – which upregulate C-C chemokine receptor type 5 (CCR5) expression – infectivity and cytopathic events were reduced in long-term non-progressors (LTNPs) HIV-1 CCR5 clones compared with those of progressors. These findings suggest that these LTNPs harbour attenuating virus mutations that interfere with infection
Study results are conflicting with regard to CCR5-D32’s association with control of HIV-1 infection. Those that argue that it is associated with disease non-progression show that HIV-infected subjects heterozygous for the allele have a significantly slower progression to AIDS, whereas several more recent studies have found that the polymorphism is absent in their LTNP cohorts (Table 2)
Summary
Who are long-term non-progressors?Years after the initiation of the 1981 AIDS pandemic, a small subset of human immunodeficiency virus type 1 (HIV-1)-infected individuals emerged with a markedly slow disease progression to AIDS. Studies that find LTNPs are more frequently heterozygous for the polymorphism than progressors and uninfected controls have shown that possessing one copy of the polymorphism results in a reduction of CCR5 expression on CD4+ T cells and is associated with slowing progression to AIDS (Dean et al, 1996; Eugen-Olsen et al, 1997; Romiti et al, 2000).
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