Abstract
The characteristics of intra-host human immunodeficiency virus type 1 (HIV-1) env evolution were evaluated in untreated HIV-1-infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term non-progressor [LTNP] patients. High-resolution phylogenetic analysis of the C2-C5 env gene sequences of the replicating HIV-1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV-1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3rd codon mutation rate was equal or even lower than that observed at the 1st and 2nd positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximum-likelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of N-linked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4-binding site (CD4bs). In addition, localized pressure in the area of the IgG-b12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3-dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV-1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV-1 infection.
Highlights
Virus-host relationships in human immunodeficiency type 1 virus (HIV-1) infection are characterized by a great complexity
Since in the absence of anti-retroviral therapy (ART), the human immunodeficiency virus type 1 (HIV-1) replication capacity (RC) is largely related to the efficiency of viral entry [5,6], the selective pressure exerted either by CTL or neutralizing antibodies can account for particular evolutionary patterns in the env gene in longterm non progressors (LTNPs) [7,8,9,10]
To assess whether allowing codons to evolve under positive selection gives a significantly better fit to the data, the log likelihood values obtained for each pair of nested models were compared using the Likelihood Ratio Test (LRT) (Additional file 1)
Summary
Virus-host relationships in human immunodeficiency type 1 virus (HIV-1) infection are characterized by a great complexity. The virus is strictly dependent on the host cell for replication, but it is constantly exposed to the immune response of the infected host. The innate and adaptive immune responses restrict HIV-1 replication after primary infection [1,2,3], efficient control of virus replication and consequent stable levels of CD4+ T-cells are observed only in a minority of patients designated longterm non progressors (LTNPs). In LTNPs, control of virus replication seems to correlate with the presence of antibodies against this critical domain, and sera from these patients show broad cross-neutralizing responses against primary HIV-1 isolates, mainly due to antibodies against this epitope [19,20,21,22]
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