Twenty years of therapy for HIV-1 infection

Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.     

Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection

Background

The clinical outcomes of short interruptions of PI-based ART regimens remains undefined.

Methods

A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.

Results

The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.

Conclusion

We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00100646","term_id":"NCT00100646"}}NCT00100646     

Persistence of VRC01-resistant HIV-1 during antiretroviral therapy

VRC01,a broadly neutralizing monoclonal antibody(bnmAb),can neutralize a diverse array of HIV-1 isolates by mimicking CD4 binding to the envelope glycoprotein gp120.We have previously demonstrated the presence of VRC01-resistant strains in an HIV-1 infected patient during antiretroviral therapy.Here,we report follow-up studies of two subsequent samples from the same patient.With genetic and phenotypic analysis of over 70 full-length molecular clones of the HIV-1 envelope,we show that VRC01-resistant HIV-1 continued to exist and change in its proportion of the infecting virus during treatment with a highly active antiretroviral therapy.Consistent with our previous observation,the resistant phenotype was associated with a single asparagine residue at position 460(N460),a potential N-linked glycosylation site in the V5 region.The persistence and continuing evolution of VRC01-resistant HIV-1 in vivo presents a great challenge to our future preventative and therapeutic interventions based on VRC01.     

HIV-1 dynamics at different time scales under antiretroviral therapy

We exploit a model that considers three compartments: blood plasma (BP), lymphoid tissue-interstitial spaces (LT-IS), and follicular dendritic cells (FDC), for the HIV-1 dynamics under the application of highly active antiretroviral therapy (HAART) which allowed us to unravel distinct viral dynamics occurring in short- (2 days), middle- (21 days), and long-term (183 days) time scales. The different time scales are determined by the viral clearance rate, the ratio of productively infected CD4⁺ T cells to chronically infected cells, and the dissociation rate of HIV-1 complexes from FDC. This generates a scenario in which, after an initial transient stage, the viral BP dynamics decouples and becomes governed by the lymphoid tissue (LT) dynamics; in a later stage, a new decoupling occurs in which the LT-IS dynamics is slaved to that of the FDC dynamics. We observed an initial increase in the viremia after HAART in a patient who did not receive protease inhibitors (PI). By means of the above-mentioned model we were able to highlight the relevant parameters which need to be estimated at three different time scales after HAART.     

Uridine metabolism in HIV-1-infected patients: effect of infection, of antiretroviral therapy and of HIV-1/ART-associated lipodystrophy syndrome

Background

Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood.

Methods

Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR.

Results

Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40–4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55–4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls.

Conclusions

HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.     

Cutting edge: Rapid recovery of NKT cells upon institution of highly active antiretroviral therapy for HIV-1 infection

CD1d-restricted NKT cells play important regulatory roles in various immune responses and are rapidly and selectively depleted upon infection with HIV-1. The cause of this selective depletion is incompletely understood, although it is in part due to the high susceptibility of CD4+ NKT cells to direct infection and subsequent cell death by HIV-1. Here, we demonstrate that highly active antiretroviral therapy (HAART) results in the rapid recovery of predominantly CD4(-) NKT cells with kinetics that are strikingly similar to those of mainstream T cells. As it is well known that the early recovery of mainstream T cells in response to HAART is due to their redistribution from tissues to the circulation, our data suggest that the selective depletion of circulating NKT cells is likely due to a combination of cell death and tissue sequestration and indicates that HAART can improve immune functions by reconstituting both conventional T cells and immunoregulatory NKT cells.     

Metabolic complications of HIV-1 antiretroviral therapy: the lipodystrophy syndrome

The lipodystrophy syndrome is one of the complications reported with increased frequency in patients with HIV-1 infection receiving antiretroviral therapy. The wide range of prevalence estimates may be due to differing definitions, methods and patient populations. We described the various pathogenic theories and the morphological and metabolic alterations associated with this syndrome. Even if no effective treatment exists, a correct lifestyle, adequate diet and physical exercise seem to be very important. Moreover drug therapies should be used with care to avoid potentially harmful interactions with antiretroviral agents. Ideally, the future effort to define the mechanism of lipodystrophy would be multidisciplinary and would involve not only experts in AIDS research but also nutritionists, endocrinologists and cardiologists.     

Antibody reactivity to HIV-1 Vpu in HIV-1/AIDS patients on highly active antiretroviral therapy

Human immunodeficiency virus type 1 (HIV-1) Vpu protein promotes both extracellular release of viral particles and degradation of CD4 in the endoplasmic reticulum. The correlation of anti-Vpu antibody (Ab) reactivity to Vpu and AIDS disease progression was studied in 162 HIV-1/AIDS patients after they had received highly active antiretroviral therapy (HAART) for 1 year. Anti-Vpu Ab reactivity was analyzed by Western blot using a recombinant Vpu protein. Results showed that at baseline (prior to initiation of HAART), 31.5% of patients (51/162) had anti-Vpu Ab. The proportion of anti-Vpu Ab in patients with CD4 counts > or =500, 200-500 and <200/mm(3) were 40.6, 34.7 and 14.3%, respectively (chi(2) test, p < 0.05). In addition, decreasing levels of anti-Vpu Ab reactivity were significantly correlated with increasing levels of HIV-1 viral load. After receiving HAART for 1 year, 7 of 111 anti-Vpu Ab-negative patients (6.3%) seroconverted (- --> + group) and 8 of 51 anti-Vpu Ab-positive (15.7%) patients became negative (+ --> - group). Among 104 anti-Vpu Ab-negative patients, 40 were selected for analysis of the VPU gene. All of them had an intact VPU gene. Patients were further divided into four groups according to their anti-Vpu Ab serostatus and anti-HIV-1 Ab was measured. The results showed that only the anti-Vpu Ab seroconverted group (- --> +) had increased serum levels of anti-HIV-1 Abs after 1 year of HAART, while the other three groups (+ --> +, - --> - and + --> -) had decreased serum levels of anti-HIV-1 Abs after 1 year of HAART (p < 0.05). In conclusion, the presence of anti-Vpu Ab is associated with improved prognosis following HIV-1 infection, and seroconversion of anti-Vpu Ab in patients on HAART indicates significant recovery of immunity.     

Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.     

Optimal timing and duration of induction therapy for HIV-1 infection

The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction–maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6–10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen. For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal. The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated. These observations have implications for both the timing and the kinds of drugs selected for induction–maintenance and therapy-intensification strategies.     

HIV-1感染的共受体

早在1984年就已发现人免疫缺陷病毒一I型（HIV－l）感染细胞是通过与细胞表面受体CDe结合而进行的,但两年后又发现表达CDe的非人类细胞不能被IlfV－l感染,因此有人认为仅有CDe作为H］V－l的受体是不够的,还必须有人类细胞特异表达的某种辅助因子。最近,一些与CDe偶联的HIV则共受体已被陆续鉴定,它们均为趋化因子（chemokjnes受体家族的成员,也正是H］V－l感染所必需的辅助因子。互作为HIV—且共受体的趋化因子受体CXCR4是第一个被发现具有I］：IV－l共受体作用的蛋白质I’］,最初称为融合素（fusin）、LESTR等。最近…     

Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption

Background

Long-term benefits of combination antiretroviral therapy (cART) initiation during primary HIV-1 infection are debated.

Methods

The evolution of plasma HIV-RNA (432 measurements) and cell-associated HIV-DNA (325 measurements) after cessation of cART (median exposure 18 months) was described for 33 participants from the Zurich Primary HIV Infection Study using linear regression and compared with 545 measurements from 79 untreated controls with clinically diagnosed primary HIV infection, respectively a known date for seroconversion.

Results

On average, early treated individuals were followed for 37 months (median) after cART cessation; controls had 34 months of pre-cART follow-up. HIV-RNA levels one year after cART interruption were −0.8 log₁₀ copies/mL [95% confidence interval −1.2;−0.4] lower in early treated patients compared with controls, but this difference was no longer statistically significant by year three of follow-up (−0.3 [−0.9; 0.3]). Mean HIV-DNA levels rebounded from 2 log₁₀ copies [1.8; 2.3] on cART to a stable plateau of 2.7 log₁₀ copies [2.5; 3.0] attained 1 year after therapy stop, which was not significantly different from cross-sectional measurements of 9 untreated members of the control group (2.8 log₁₀ copies [2.5; 3.1]).

Conclusions

The rebound dynamics of viral markers after therapy cessation suggest that early cART may indeed limit reservoir size of latently infected cells, but that much of the initial benefits are only transient. Owing to the non-randomized study design the observed treatment effects must be interpreted with caution.     

Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations

Background  

Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood.     

Study of HIV-1 drug resistance in patients receiving free antiretroviral therapy in China

To investigate the prevalence of drug-resistance mutations, resistance to antiretroviral drugs, and the subsequent virological response to therapy in treatment-naive and antiretroviral-treated patients infected with HIV/AIDS in Henan, China, a total of 431 plasma samples were collected in Queshan county between 2003 and 2004, from patients undergoing the antiretroviral regimen Zidovudine + Didanosine + Nevirapine (Azt+Ddi+Nvp). Personal information was collected by face to face interview. Viral load and genotypic drug resistance were tested. Drug resistance mutation data were obtained by analyzing patient-derived sequences through the HIVdb Program (http://hivdb.stanford.edu). Overall, 38.5% of treatment-naive patients had undetectable plasma viral load (VL), the rate significantly increased to 61.9% in 0 to 6 months treatment patients (mean 3 months) (P<0.005) but again significantly decrease to 38.6% in 6 to 12 months treatment patients (mean 9 months) (P<0.001) and 40.0% in patients receiving more than 12 months treatment (mean 16 months) (P<0.005). The prevalence of drug resistance in patients who had a detectable VL and available sequences were 7.0%, 48.6%, 70.8%, 72.3% in treatment-naïve, 0 to 6 months treatment, 6 to 12 months treatment, and treatment for greater than 12 months patients, respectively. No mutation associated with resistance to Protease inhibitor (PI) was detected in this study. Nucleoside RT inhibitor (NRTI) mutations always emerged after non-nucleoside RT inhibitor (NNRTI) mutations, and were only found in patients treated for more than 6 months, with a frequency less than 5%, with the exception of mutation T215Y (12.8%, 6/47) which occurred in patients treated for more than 12 months. NNRTI mutations emerged quickly after therapy begun, and increased significantly in patients treated for more than 6 months (P<0.005), and the most frequent mutations were K103N, V106A, Y181C, G190A. There had been optimal viral suppression in patients undergoing treatment for less than 6 months in Queshan, Henan. The drug resistance strains were highly prevalent in antiretroviral-treated patients, and increased with the continuation of therapy, with many patients encountering virological failure after 6 months therapy.     

Kinetics of the changes of lymphocyte subsets defined by cytokine production at single cell level during highly active antiretroviral therapy for HIV-1 infection

The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets.