Background: It is under debate whether HIV-disease progresses more rapidly in patients (pts) harboring viruses with low- or with high-viral diversity. For this reason, we studied plasma HIV-env diversity in HIV-infected pts prior to long-term combination antiretroviral therapy (ART). We then tested whether pretreatment diversities predicted virological control after STI and cellular as well as humoral immune responses.

Methods: Plasma was obtained from 26 HIV-infected pts before any ART. Pts then were on successful ART for a median of 31 (range 19–48) months (mos). Subsequently, they were enrolled in the Swiss Spanish Intermittent Therapy Trial and underwent 4 STI cycles (2 wks interruption, 8 wks re-treatment) followed by ART stop at wk 40 for 7 wks up to > 1 year. HIV-RNA extracts were subjected to RT-PCR, cloning (16 clones/sample), and bidirectional ABI sequencing of the env C2V3C3 domain. Phylogenetic analyses were done with PHYLIP 3.6 and Mega 2.0. Five (5) pts were excluded: PCR failed in 2 cases (1 subtype C, 1 E/CRF1), protocol violation of 2 pts, start of ART in 1 pt during primary infection.

Results: Pre-treatment intra-patient HIV-env nucleotide sequence diversities (Dnt) ranged from 0.7%–5.5%, amino acid diversities (Daa) from 1.0%–9.4%. Seven (7) out of 21 pts contained plasma viremia at low levels after final ART stop. Those had significantly lower pretreatment diversities (Dnt 1.7 ±0.9% vs 3.1 ±1.3%, p = 0.03; Daa 3.1 ±1.7% vs 5.9 ±2.4%, p = 0.02). They also showed lower HIV DNA levels in peripheral blood cells (p = 0.02) at the beginning of STI. Moreover, higher plasma neutralization activity against autologous virus was found to be associated with lower pretreatment diversity (p = 0.06 for Dnt and Daa). However, no association between diversity, anti gp120 titers, HIV specific CTL-, and T-help responses were found. Pts controlling viremia showed significantly higher neutralization activity than non-controllers (p = 0.02).

Conclusions: The finding of lower viral pre-treatment diversity (both Dnt and Daa) in pts with stronger spontaneous virological control after the last STI does not favor the hypothesis that a slower rate of disease progression is associated with a broader immunologic response. On the contrary, higher neutralizing antibody activity was found in pts controlling viremia, when no difference between CTL and T-help responses was present between controllers and non-controllers.