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Background: HIV genetic diversity implicates major challenges for the control of viral infection by the immune system and for the identification of an effective immunotherapeutic strategy. With the present case report we underline as HIV evolution could be effectively halted by early antiretroviral treatment (eART). Few cases supported this evidence due to the difficulty of performing amplification and sequencing analysis in long-term viral suppressed patients. Here, we reported the case of limited HIV-1 viral evolution over time in a successful early treated child., Case Presentation: A perinatally HIV-1 infected infant was treated within 7 weeks of age with zidovudine, lamivudine, nevirapine and lopinavir/ritonavir. At antiretroviral treatment (ART) initiation HIV-1 viral load (VL) and CD4 percentage were >500,000 copies/ml and 35%, respectively. Plasma genotypic resistance test showed a wild-type virus. The child reached VL undetectability after 33 weeks of combination antiretroviral therapy (cART) since he maintained a stable VL <40copies/ml. After 116 weeks on ART we were able to perform amplification and sequencing assay on the plasma virus. At this time VL was <40 copies/ml and CD4 percentage was 40%. Again the genotypic resistance test revealed a wild-type virus. The phylogenetic analysis performed on the HIV-1 pol sequences of the mother and the child revealed that sequences clustered with C subtype reference strains and formed a monophyletic cluster distinct from the other C sequences included in the analysis (bootstrap value >90%). Any major evolutionary divergence was detected., Conclusions: eART limits the viral evolution avoiding the emergence of new viral variants. This result may have important implications in host immune control and may sustain the challenge search of new personalized immunotherapeutic approaches to achieve a prolonged viral remission.

Background: HIV resistance affects virological response to therapy and efficacy of prophylaxis in mother-to-child-transmission. The study aims to assess the prevalence of HIV primary resistance in pregnant women naïve to antiretrovirals., Methods: Cross sectional baseline analysis of a cohort of HIV + pregnant women (HPW) enrolled in the study entitled Antiretroviral Management of Antenatal and Natal HIV Infection (AMANI, peace in Kiswahili language). The AMANI study began in May 2010 in Dodoma, Tanzania. In this observational cohort, antiretroviral treatment was provided to all women from the 28th week of gestation until the end of the breastfeeding period. Baseline CD4 cell count, viral load and HIV drug-resistance genotype were collected., Results: Drug-resistance analysis was performed on 97 naïve infected-mothers. The prevalence of all primary drug resistance and primary non-nucleoside reverse-transcriptase inhibitors resistance was 11.9% and 7.5%, respectively. K103S was found in two women with no M184V detection. HIV-1 subtype A was the most commonly identified, with a high prevalence of subtype A1, followed by C, D, C/D recombinant, A/C recombinant and A/D recombinant. HIV drug- resistance mutations were detected in A1 and C subtypes., Conclusion: Our study reports an 11.9% prevalence rate of primary drug resistance in naïve HIV-infected pregnant women from a remote area of Tanzania. Considering that the non-nucleoside reverse-transcriptase inhibitors are part of the first-line antiretroviral regimen in Tanzania and all of Africa, resistance surveys should be prioritized in settings where antiretroviral therapy programs are scaled up.

The pathogenetic bases of HAART-associated lipodystrophy are still poorly known, even if it is clear that adipose tissue and its metabolism are sensitive to antiretroviral therapy alone and/or in combination with HIV infection. The NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression, morphogenesis and tumorigenesis. We investigated the possible involvement of NEED8 in adipogenesis and, consequently, in HIV-related lipodystrophy. One hundred HIV-1-infected patients were included in the study. Using an in vitro model of adipogenesis we evaluated the effects on adipogenesis of the forced expression of NEDD8 together with efavirenz, stavudine, saquinavir, amprenavir and indinavir, belonging to the three main classes of anti-HIV medications. We showed that NEDD8 expression level is higher in the peripheral blood of HIV patients developing lipodystrophy. Coherently, forced expression of NEDD8 in an in vitro model of adipogenesis was able to perturb expression of some key proteins involved in adipogenesis, such as C/EBPalpha and PPARgamma, possibly acting throughout the NEDD8/p27/beta-catenin pathway. Moreover, three out of five evaluated drugs were able to affect adipocyte differentiation: efavirenz, stavudine and saquinavir. Finally, we have shown that NEDD8 was expressed in the fat tissue of lipodystrophic patients, being significantly higher in the lipodystrophic patients with respect to the controls, thus further confirming the altered NEDD8 expression in the fat tissue of HIV-infected patients affected by lipodystrophy. Taken together, our data support the hypothesis of an implication of NEDD8 through p27 and beta-catenin pathways in the disruption of adipogenesis and consequent lipodystrophy in patients affected by HIV infection under HAART therapy with qualitative and quantitative differences according to diverse antiretroviral treatments. These evidences indicate the NEDD8/beta-catenin/p27 pathway as a possible molecular target for prevention of lipodystrophy development in patients under HAART therapy.

Early recognition of virologic failure in patients with extensive drug resistance receiving salvage-HAART is essential to avoid exposure to subinhibitory regimens. We studied plasma viral load (PVL) decline and rates of drug-resistance mutation (DRM) accumulation in such patients. A prospective, 48 week study of 38 heavily pretreated patients receiving genotypic resistance testing (GRT)-guided HAART was conducted. The rate of PVL decline was studied by weekly PVL determinations. To assess DRM accumulation, serial GRTs were performed in all nonresponders (never reaching PVL <50 or two PVLs >50 copies/ml after suppression). Over 48 weeks, 10 patients (26%) were nonresponders. Receiving less then two fully active drugs and having an elevated number of PI and NRTI mutations at baseline were strongly associated with virologic failure. There was no evidence of a difference in the change from baseline PVL to week 1 and 2 between responders and nonresponders. By contrast, PVL reductions from week 2 to week 3 and thereafter were significantly greater for responders (p < 0.01). Among nonresponders, the incidence rates per patient-month (95% CI) of emergent DRM were 0.67 (0.13-1.20), 0.40 (0.00-0.74), and 0.37 (0.00-0.75) at weeks 4, 8, and 24, respectively. Having limited baseline resistance, receiving at least two fully active drugs, and showing constant PVL reductions from week 2 to week 3 and thereafter were predictive of virologic response. In contrast, early changes in PVL levels were not. Virologic failure was associated with detection of emergent DRMs. Virologic rebound in patients on salvage-HAART should be addressed aggressively.

Background: The V118I mutation is included in the nucleoside analogue mutations (NAMs) set. It contributes to thymidine-analogue resistance and, consequently, to resistance to the whole nucleoside reverse transcriptase inhibitor (NRTI) class. We focused on the V1181 mutation in order to evaluate factors associated with its detection and its relationship with HIV progression., Methods: Clinical and laboratory data at genotypic resistance test (GRT) of highly active antiretroviral therapy-failing patients were collected and their association with the V1181 mutation was analysed. Patients were also followed over time to determine factors related to progression to a new AIDS-related event or death., Results: Of the 792 patients included, 114 (14.4%) carried the V118I mutation. In univariate analysis, the V118I mutation was significantly associated with a higher HIV RNA level, lower CD4+ T-cell count, Centers for Disease Control and Prevention (CDC) stage C, higher number of pre-GRT regimens and class-wide resistance (CWR) to NRTIs, protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Higher numbers of pre-GRT regimens and NRTI CWR were also associated in the multivariable analysis. Within the post-GRT observation period of up to 6 years (median: 72 months; interquartile range: 33-109) 107 events (58 new AIDS-related diseases and 49 deaths) were observed. Using the Cox proportional hazard model and the major clinical, behavioural and laboratory data, the V118I mutation was found to be associated with the endpoint (hazard ratio: 1.93, 95% confidence interval: 1.06-3.50; P=0.031). Other factors associated with disease progression were CDC stage C and lower CD4+ T-cell count at GRT., Conclusions: The analysis of our observational database suggests that the onset of the V118I mutation after treatment failure is unfavourable for the patient and can be considered a strong marker of disease progression.

The emergence of HIV-resistant strains generally occurs during treatment failure. A high rate of viral replication, low patient adherence to therapy, poor drug absorption or increased drug metabolism may be related to treatment failure and favour the onset of resistance. Recently, despite the absence of detectable HIV viral load in plasma, the importance of the persistence of HIV replication in other reservoirs has been underlined. Paired semen and plasma specimens stored from HIV male patients were tested using the LiPA assay, detecting genotype mutations related to Nucleoside Reverse Transciptase Inhibitors (NRTI) resistance. Overall, 32 paired semen and plasma samples were analyzed. The presence of HIVsequences was determined in 13 paired specimens (40.6%). Sixteen semen and 10 plasma specimens failed to amplify. At least one mutation was identified in the plasma of 77.8% of treated and 50.0% of naive patients. Similarly, mutations were identified in the semen of 66.7% of treated and 50.0% of untreated patients. Different mutation patterns between the two compartments were found in 46.2% of patients. The use of rapid assessment of HIV resistance in plasma and semen may be useful in some situations, such as HIV infection transmitted by sexual contact. Our data reinforce the evidence that, regarding HIV replication, the male genital tract must be considered as a separate compartment from the plasma.

To determine the variability of genotypic human immunodeficiency virus (HIV) type 1 drug-resistance interpretation by available expert systems and its clinical implications, 261 subjects for whom a potent antiretroviral regimen was failing who were starting salvage therapy were evaluated. The association of the genotypic susceptibility score (GSS) of the salvage regimen, according to 11 interpretation systems, with HIV RNA outcomes for 6 months was examined. GSS was highly variable, as determined by the different interpretation systems, and showed independent correlation with changes from baseline HIV RNA levels at 6 months with 5 systems--Stanford hivdb, GuideLines 3.0, Retrogram 1.4, HIVresistanceWeb, and São Paulo University. Most GSSs predicted virologic response in regimens containing stavudine, lamivudine, efavirenz, or indinavir. Selected systems predicted response in regimens containing didanosine, abacavir, or nelfinavir, and no system predicted outcome of boosted protease inhibitors. GSSs predicted changes in HIV RNA levels better in adherent patients than in nonadherent individuals. Interpretation may be improved, and knowledge should be used uniformly throughout different expert systems.

A rebound in the plasma and seminal viral load was detected in 12 patients after the interruption of effective highly active antiretroviral therapy. The viral rebound was generally higher in plasma, although the highest level observed during interruption was higher in semen in two patients. The reintroduction of therapy was followed by an overall decrease in HIV-RNA in plasma and semen. One to 2 months after restarting treatment, four out of seven patients showed undetectable HIV-RNA in semen.

Single witness: HIV-1 drug resistance assays have been shown to be of value for guiding antiretroviral therapy (ART) decisions. Different tissues or body fluids in which HIV-1 can reside may contain viruses with distinct characteristics. HIV-1 variants with genotypic resistance markers are present in the male genital tract and evolve over time on incompletely suppressive ART. The magnitude of decline in the semen HIV-RNA level in with therapy is usually similar to the effect of treatment on the blood viral burden. Not all men on ART have complete suppression of HIV-1 replication in genital tract; thus, they may shed resistant HIV-1 strains. Failure of treatment to suppress HIV-RNA levels in the blood is common, resulting in the selection of resistant HIV-1 variants. Sexual transmission of resistant variants may have a negative impact on treatment outcome in newly infected individuals and on the spread of the diseases within a population. The use of rapid assessment of HIV resistance in plasma and semen may be useful in some situations, e.g. HIV transmitted infection by sexual contact from a viraemic patient. The recognition of resistant HIV isolates in the blood and semen of patients receiving ART leads to the question of the potential role of resistance testing. In many but not all infectious diseases, the choice of therapy is guided by sensitivity testing. Recent data suggest that testing the drug sensitivity of viral isolates from the blood can benefit patient management and response to therapy, albeit at considerable cost. However, since drug resistance may evolve independently in blood and semen, the public health benefits of such testing are unproven.

Objective: To determine the effectiveness of antiretroviral therapy in controlling cerebrospinal fluid (CSF) HIV-1 replication and to assess factors related to virological response in advanced patients., Design: A cross-sectional and longitudinal study., Methods: Consecutive paired CSF and plasma samples from HIV-1-infected patients were collected before starting or changing highly active antiretroviral therapy (HAART)., Results: In the cross-sectional analysis 75 patients were included, 55 (73%) with neurological disease, 28 (37%) naive for antiretroviral agents. A significant correlation between plasma and CSF levels at baseline was observed only in antiretroviral-experienced patients. The absence of neurological disease, lower plasma HIV-1 load and a previous exposure to indinavir were all associated with a baseline CSF HIV-1-RNA level less than 80 copies/ml at multivariate analysis. In 29 patients included in the longitudinal study a significant reduction in CSF HIV-1 RNA was observed. Plasma HIV-1-RNA change, CSF HIV-1-RNA level at baseline, overall months of antiretroviral treatment and the magnitude of difference between plasma and CSF HIV-1-RNA levels were all correlated to CSF HIV-1-RNA change during treatment. A significant difference in the magnitude of CSF HIV-1-RNA reduction was observed according to naive status and to the use of three or more drugs penetrating the blood-brain barrier., Conclusion: HAART effectively reduces HIV-1 replication in CSF. A variable response to antiretroviral therapy was observed in CSF, reflecting a different compartmentalization of infection during treatment. Naive status and the use of CNS-penetrating drugs substantially enhance antiviral response. A negative interaction between virological response and the duration of antiretroviral treatment suggests long-term selection of drug-resistant CSF HIV-1 strains.

A cluster of HIV-1 infection has been identified in Libya in 1999, involving 402 children admitted to "El-Fath" Children's Hospital in Benghazi (BCH) during 1998 and 19 of their mothers. Nosocomial transmission has been indicated as responsible for the spread of infection. Out of this group, 104 children and 19 adult women have been followed at the National Institute for Infectious Diseases L. Spallanzani in Rome during 1 year. At BCH, all children had received intravenous infusions but not blood or blood products. A single child receiving a blood transfusion in 1997 and the 17 infected mothers were never hospitalized in Benghazi. In addition, two nurses were diagnosed as HIV-1 infected. In 40 subjects out of this group HIV-1 gag, env, and pol fragments were amplified and sequenced. The phylogenetic analyses showed that a monophyletic recombinant HIV-1 form CRF02-AG was infecting all of the HIV-1-seropositive patients admitted at BCH with no close similarities to the other CRF02-AG reported to GenBank. A different strain was found in the child infected by blood transfusion. The data thus suggest a highly contagious nosocomial spread of HIV-1 infection and possibly transmission of the virus from child to mother during breastfeeding in connection with primary HIV-1 infection.