Lewin SR, Murray JM, Solomon A, et al. Virologic determinants of success after structured treatment interruptions of antiretrovirals in acute HIV-1 infection
ABSTRACT Latently infected resting memory CD4 T cells are thought to be the major reservoir that contributes to rebound viremia after cessation of antiretrovirals (ARVs). Commencing ARVs during primary HIV-1 infection (PHI) may limit the size of the latent pool and lead to improved control of viral replication during structured treatment interruption (STI).
Individuals with PHI (n = 59) were randomized to receive ARVs with or without hydroxyurea. After STI, a good response was defined as maintenance of HIV-1 RNA <5000 copies/mL for 24 weeks off therapy. In a detailed prospective virologic substudy (n = 19), integrated HIV-1 DNA, total HIV-1 DNA, and cell-associated HIV-1 unspliced (US) RNA were quantified using a real-time polymerase chain reaction assay.
The plasma HIV-1 RNA 12 weeks after the initiation of ARVs was significantly lower in good responders (n = 7) compared with poor responders (n = 12) (P = 0.005). There were no significant differences between good and poor responders in integrated HIV-1 DNA, HIV-1 DNA, and HIV-1 US RNA. Integrated HIV-1 DNA before initiation of ARVs was strongly correlated with plasma HIV-1 RNA at week 12 (P = 0.006, r = 0.81).
HIV-1 RNA measured 12 weeks after initiation of ARV was the only virologic variable associated with viral rebound after treatment interruption in PHI.
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- "However, in another prospective study of PHI, eight EC were identified amongst 211 untreated PHI subjects (out of a total of 964 subjects enrolled), and there was no significant difference in symptomatic PHI (Goujard et al., 2009), but there was a clearly significant difference in HIV RNA viral load. Similarly, we found that patients who exhibited better control of HIV RNA, during treatment interruption after 6–12 months cART commenced during PHI, had a significantly lower HIV RNA level at baseline, by multivariate analysis (Bloch et al., 2006), and this correlated with lower levels of integrated HIV DNA prior to cART (Lewin et al., 2008). Another large natural history study showed that viral control was established in the majority of EC within 1 year of seroconversion , but characteristics of PHI were not reported for this cohort (Okulicz et al., 2009). "
ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T cells in vitro, in response to p24. In some cases, the responding CD4 T cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the ∆32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27 and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far.Frontiers in Immunology 04/2013; 4:95. DOI:10.3389/fimmu.2013.00095
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ABSTRACT: Antiretroviral therapy in early HIV infection may enhance outcome and viral control may be better in acute versus recent infection 24 weeks after treatment interruption. A prospective trial of treatment stratified by acute versus recent HIV-1 infection. If HIV viral load <50 copies/ml after at least 52 weeks, treatment was interrupted. If viremia rebounded, treatment and interruption were repeated. The primary endpoint was maintaining viral load less than 5000 copies/ml for 24 weeks following treatment interruption. Of the 121 patients enrolled at 15 sites, ninety-five percent were men, median age was 34 years; 69% were white. Median viral load was higher in acute HIV-1 infection (210 000 copies/ml) than recent HIV-1 infection (43 000 copies/ml). The 73 primary endpoint patients (28 acute HIV-1 infection, 45 recent HIV-1 infection) had significantly higher baseline CD4 T-cell counts (P = 0.044) and lower viral load (P = 0.016). The primary endpoint was achieved in 29 (40%) of the 73 and in 24% of the 121 enrolled overall. There was no significant outcome difference (P = 0.81) between the acute HIV-1 infection [43%, 95% confidence interval (CI) 24-63%] and recent HIV-1 infection (38%, 95% CI 24-53%) groups. Differences after longer follow-up can not be ascertained by this trial. Baseline viral load less than 100 000/ml 22/46 (48%) compared with more than 100 000/ml, 7/27 (26%) and higher baseline CD4 immune activation predicted success. Forty percent of patients treated during acute HIV-1 infection or recent HIV-1 infection sustained a viral load less than 5000 copies/ml after 24 weeks of treatment interruption.AIDS (London, England) 08/2009; 23(15):1987-95. DOI:10.1097/QAD.0b013e32832eb285 · 6.56 Impact Factor
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ABSTRACT: Gene therapy represents a new treatment paradigm for HIV that is potentially delivered by a safe, once-only therapeutic intervention. Using mathematical modelling, we assessed the possible impact of autologous haematopoietic stem cell (HSC) delivered, anti-HIV gene therapy. The therapy comprises a ribozyme construct (OZ1) directed to a conserved region of HIV-1 delivered by transduced HSC (OZ1+HSC). OZ1+HSC contributes to the CD4+ T lymphocyte and monocyte/macrophage cell pools that preferentially expand under the selective pressure of HIV infection. The model was used to predict the efficacy of OZ1 in a highly active antiretroviral therapy (HAART) naïve individual and a HAART-experienced individual undergoing two structured treatment operations. In the standard scenario, OZ1+HSC was taken as 20% of total body HSC. For a HAART-naïve individual, modelling predicts a reduction of HIV RNA at 1 and 2 years post-OZ1 therapy of 0.5 log(10) and 1 log(10), respectively. Eight years after OZ1 therapy, the CD4+ T-lymphocyte count was 271 cells/mm(3) compared to 96 cells/mm(3) for an untreated individual. In a HAART-experienced individual HIV RNA was reduced by 0.34 log(10) and 0.86 log(10) at 1 and 2 years. The OZ1 effect was maximal when both CD4+ T lymphocytes and monocytes/macrophages were protected from successful, productive infection by OZ1. The modelling indicates a single infusion of HSC cell-delivered gene therapy can impact on HIV viral load and CD4 T-lymphocyte count. Given that gene therapy avoids the complications associated with HAART, there is significant potential for this approach in the treatment of HIV.The Journal of Gene Medicine 12/2009; 11(12):1077-86. DOI:10.1002/jgm.1401 · 2.47 Impact Factor