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PubMed2004

Lack of evidence for protease evolution in HIV-1-infected patients after 2 years of successful highly active antiretroviral therapy.

The mechanisms involved in maintaining a latent replication-competent integrated human immunodeficiency virus type 1 (HIV-1) reservoir after successful highly active antiretroviral therapy (HAART) have not been fully described. The objective of this study was to assess whether low-level, persistent HIV-1 replication can be detected in the protease gene, in 10 HIV-1-infected patients who have undergone 2 years of successful HAART. Peripheral blood mononuclear cells (PBMCs) were collected from 10 HIV-1-infected patients receiving a triple-drug combination therapy (2 nucleoside analogues and 1 protease inhibitor). HIV-1 RNA levels and CD4+ and CD8+ T cell counts were longitudinally determined during a follow-up period of 108 weeks. Similarly, proviral fragments of the protease-coding region, obtained at baseline and at week 108 of HAART, were amplified by polymerase chain reaction from PBMCs, and 10-25 individual clones were sequenced for each time point. Only 1 of 271 individual protease clones showed a major resistance substitution (M46I [patient D]). Phylogenetic analysis revealed that, in all patients, the genetic distances from the deduced most recent common ancestor, in samples obtained at week 108 of HAART, were not longer than those in samples obtained at baseline. Moreover, the pattern of amino acid divergence during therapy showed an absence of positive selection in the protease-coding region. Taken together, these results show a lack of clinically relevant evolution in the protease-coding region after 2 years of successful HAART.

Amino Acid Sequence↗
PubMed2001

Maximum likelihood analysis of adaptive evolution in HIV-1 gp120 env gene.

Every functional protein appears to have some conserved amino acids which are critically important to the basic structure and function of the protein and thus under purifying selection. Some proteins also have variable amino acids which, when changed, offer a selective advantage, and thus undergo adaptive evolution. These amino acids are also important to the structure and function of the protein, although in a different way. It seems that the selective pressure in every protein varies among sites. Maximum likelihood models developed recently for comparison of silent and replacement nucleotide substitution rates allow for variable selective pressures among amino acid sites, and provide a powerful approach to studying the evolutionary process of protein-coding genes. This paper applies the likelihood models to analyze a data set of 186 HIV-1 gp120 env gene sequences for comparison with a previous analysis of the same data set. The maximum likelihood analysis identified a number of sites under positive selection, some in the conserved regions of the protein.

Adaptation, Physiological↗
PubMed2002

Longitudinal evolution of HIV-1-associated lipodystrophy is correlated to serum cortisol:DHEA ratio and IFN-alpha.

BACKGROUND: We have previously shown that lipid alterations in HIV-1-associated lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone (DHEA) and increased cortisol:DHEA ratio and IFN-alpha levels. OBJECTIVE: To evaluate in a longitudinal study whether steroid and cytokine modifications are associated with the evolution of physical changes and lipid alterations associated with LD. METHODS: Thirty-four HIV-1-positive men were followed during 32.5 +/- 4.0 months and tested at four time-points. The patients were subdivided into five groups according to physical changes and anthropometric measurements: LD-negative, initially LD-negative becoming LD-positive, LD-positive unchanged, aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and cytokines were measured and compared with baseline values. RESULTS: (1) LD aggravation is associated with persistent elevated lipids, a decrease in serum DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN-alpha. (2) LD improvement is associated with normalization of serum lipids, an increase in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization of IFN-alpha levels. (3) In LD-positive men evolution of VLDL cholesterol is negatively correlated with DHEA (r = -0.56, P < 0.01) and positively with cortisol:DHEA ratio (r = 0.62, P < 0.004) and with IFN-alpha (r = 0.57, P < 0.01). (4) The switch to LD is associated with a decrease in serum DHEA. (5) Patients who remained LD-negative maintained normal lipids, elevated cortisol and DHEA, and normal cortisol:DHEA ratio and normal levels of IFN-alpha. CONCLUSIONS: This study indicates that cortisol:DHEA ratio and serum IFN-alpha levels are closely associated with clinical evolution and atherogenic lipid alterations in LD.

Adult↗
PubMed1995

Genotypic evolution of HIV-1 isolates from patients after a switch of therapy from zidovudine to didanosine.

The existence of zidovudine (ZDV)-resistant and didanosine (ddI)-resistant human immunodeficiency-1 (HIV-1) variants mutated in the reverse transcriptase (RT) gene has been previously demonstrated. In this study, we tried to follow up the genotypic changes in the RT after the switch of therapy from ZDV to ddI. We studied HIV-1 isolates from 11 patients undergoing ddI therapy. Genotypic data were obtained with differential polymerase chain reaction (PCR) and with direct sequencing after PCR. The prevalence of ZDV resistance-related mutations showed a very slow decrease, particularly when patients had been treated with ZDV for a long time. The appearance of a mutation at codon 74 seemed to be independent of the presence or absence of ZDV resistance-related mutations. The broad genotypic heterogeneity of the isolates and the complexity of the evolution in one patient's isolates plead for large sequencing studies of the RT genome in new therapeutic approaches.

Base Sequence↗
PubMed2001

Evidence for positive selection driving the evolution of HIV-1 env under potent antiviral therapy.

In HIV-infected individuals treated with potent antiretroviral therapy, viable virus can be isolated from latently infected cells several years into therapy, due to the long life of these cells, ongoing replication replenishing this population, or both. We have analysed the V3 region of the HIV-1 env gene isolated from six patients who have undergone 2 years of potent antiretroviral therapy without frank failure of viral suppression. We show that in two (and possibly three) patients, the sequence changes between baseline virus and virus isolated from infected cells persisting 2 years into infection result from positive selection driving adaptive evolution, occurring either prior to or during therapy. Our analyses suggest low-level replication despite absence of drug resistance due to drug sanctuary sites, or to low-level ongoing replication in the presence of alterations in the selective environment during therapy, perhaps due to a decline in HIV-specific immune responsiveness or changes in target cell pools. In one patient, genetic divergence between baseline plasma and infected cells isolated during therapy may reflect the long half-life of some of these persistent cell populations and the divergence of viral subpopulations that occurred prior to therapy.

Amino Acid Sequence↗
PubMed1993

Psychosocial factors and clinical evolution in HIV-1 infection: a longitudinal study.

The aim of the study was to assess the relationship between the initial psychosocial situation and the probability of later symptom development in HIV-1 infection. One hundred HIV-1 seropositive subjects, 79 in Stage III (LAS) and 21 in Stage II (asymptomatic), were examined both immunologically (CD4+, Skin Test) and psychologically (test battery). Follow-up at 6 and 12 months involved clinical and immunological reassessment of subjects, who were then classified as fully symptomatic (S, Stage IV) or unchanged (U). The two groups were compared through ANOVA on initial psychosocial measures, while stepwise logistic multiple regression was employed to assess the predictive value of psychosocial measures on clinical and immunological evolution. Psychosocial measures most clearly showing an association with clinical evolution were Denial/Repression attitudes (negatively) and Fighting Spirit (positively), whereas aspects of Hardiness and Social Support showed an effect in interaction with initial CD4+ levels. No stable results were obtained on immunologic evolution. The two groups (U and S) did not show significant differences on other independent variables, with the exception of age.

Adult↗
PubMed2004

Evolution of HIV-1-related conjunctival molluscum contagiosum under HAART: report of a bilaterally manifesting case and literature review.

PURPOSE: To present a rare case of bilateral conjunctival molluscum contagiosum (MC) in an HIV-positive individual who had unilateral lesion excision before induction of highly active antiretroviral therapy (HAART), and to discuss the pathophysiological consequences of immune restoration. METHODS CASE REPORT: A 40-year-old male Caucasian presented with atypical, bilateral lesions of the limbal conjunctiva due to MC. Before the induction of HAART, nodules in the left eye were excised whilst the single lesion in the right eye was left untouched. RESULTS: The clinical diagnosis of conjunctival MC was confirmed histopathologically. Six months after the induction of HAART, the untouched lesion (right eye) had regressed and there was pronounced local injection of the conjunctiva. MC lesions did not recur after excision (left eye), and signs of inflammation were absent. CONCLUSION: Conjunctival MC is rare and associated with immune deficiency. To the best of our knowledge, the presented case is the first reported instance of bilateral, multi-lesional MC of the conjunctiva in an HIV-positive patient undergoing HAART. Attention must be paid to the possible complications associated with the restoration of immunocompetence.

Adult↗
PubMed2004

The evolution of HIV and its consequences.

Since the beginning of the AIDS epidemic in 1981, HIV-1 has demonstrated an amazing ability to mutate. HIV-1 was introduced into the human population in the early to mid twentieth century in central Africa. During ensuing decades, this extraordinary mutational capacity has resulted in the circulation of HIV-1 strains that are quite different from one another, yet still remarkably pathogenic. The potential impact of this viral diversity on treatment, monitoring,and vaccine development is discussed.

AIDS Vaccines↗
PubMed1997

The viral envelope in the evolution of HIV: a hypothetical approach to inducing an effective immune response to the virus.

The human immunodeficiency virus (HIV) is 'perceived' by the host immune system as partly-self because of the presence of host cell wall membrane on the viral envelope. This perception leads to an ineffective immune response to the virus. It is proposed that only viral core antigens without the envelope will be perceived as non-self by the host immune system and can provoke an effective immune response. In normal uninfected persons, core antigens could therefore serve as a vaccine. In HIV infected persons, uncommitted immunocytes from the peripheral leucocytes freed from antibodies will in vitro process autologous viral core antigens as non-self antigens and lead to an effective immune response against the HIV when reinjected into the patient. The use of autologous viral core antigens provides, at the same time, a means for testing viral core antigens as possible vaccines without any risk to a third person. This immunotherapy of the HIV, when confirmed, will support core antigens as possible vaccines and could also be applied to the large group of retroviral and other enveloped viruses that cause chronic infections and malignant tumours in man and animals, with considerable benefits to human and animal health.

AIDS Vaccines↗
PubMed2001

The metabolic puzzle during the evolution of HIV infection.

Abnormalities in energy, protein, lipid and glucose metabolism have been described in HIV patients since the beginning of the epidemic. With the new antiretroviral agents, nutritional status and survival have improved dramatically. However, since these therapies were introduced, there have been more descriptions of metabolic abnormalities, some of which were similar to and others of which were in conflict with those reported in previous years. This paper reviews the complexity of the metabolic abnormalities in HIV infections before and after the introduction of highly active antiretroviral therapy, and discusses such etiopathogenic mechanisms as secondary infections, antiretroviral drugs and persistent immune activation, which may be involved in these derangements.

Anti-HIV Agents↗
PubMed1997

Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains.

The chemokine receptor CXCR4 functions as a fusion coreceptor for T cell tropic and dual-tropic HIV-1 strains. To identify regions of CXCR4 that are important for coreceptor function, CXCR4-CXCR2 receptor chimeras were tested for the ability to support HIV-1 envelope (env) protein-mediated membrane fusion. Receptor chimeras containing the first and second extracellular loops of CXCR4 supported fusion by T tropic and dual-tropic HIV-1 and HIV-2 strains and binding of a monoclonal antibody to CXCR4, 12G5, that blocks CXCR4-dependent infection by some virus strains. The second extracellular loop of CXCR4 was sufficient to confer coreceptor function to CXCR2 for most virus strains tested but did not support binding of 12G5. Truncation of the CXCR4 cytoplasmic tail or mutation of a conserved DRY motif in the second intracellular loop did not affect coreceptor function, indicating that phosphorylation of the cytoplasmic tail and the DRY motif are not required for coreceptor function. The results implicate the involvement of multiple CXCR4 domains in HIV-1 coreceptor function, especially the second extracellular loop, though the structural requirements for coreceptor function were somewhat variable for different env proteins. Finally, a hybrid receptor in which the amino terminus of CXCR4 was replaced by that of CCR5 was active as a coreceptor for M tropic, T tropic, and dual-tropic env proteins. We propose that dual tropism may evolve in CCR5-restricted HIV-1 strains through acquisition of the ability to utilize the first and second extracellular loops of CXCR4 while retaining the ability to interact with the CCR5 amino-terminal domain.

Cell Fusion↗
PubMed1998

Short-term evolution of HIV-1 viraemia and CD4+ cell counts in patients who have a primary mutation to zidovudine.

OBJECTIVE: To investigate the different responses to antiretroviral treatment including zidovudine, of patients harbouring HIV with primary resistance to zidovudine, serum viral load, and CD4+ cell counts, for 24 weeks in a group of antiretroviral-naive patients with the codon 215 mutation of the HIV pol gene and in a control group at the start of treatment. DESIGN: A case-control retrospective study (1989-1996). METHOD: Nineteen out of 210 patients previously studied harboured the codon 215 mutation, had a self-reported compliance with treatment, a minimum follow-up of 24 weeks, and were treated with zidovudine alone or in combination with other nucleoside analogues. These patients were matched with 19 patients with wild-type strains at entry by initial CD4+ cell counts, clinical status, and antiretroviral treatment. RESULTS: During the first 12 weeks, CD4+ cell counts increased (76+/-26 and 64+/-26 x 10(6)/l in wild-type and mutant virus-infected groups, respectively), decreasing slightly until week 24, although no significant differences were found between the two groups studied. Serum viral load decreased in both groups (change in serum viral load of 0.80+/-0.11 log10 and 0.87+/-0.26 log10 copies/ml, wild-type and mutant virus-infected, respectively), although no significant differences were found between groups. CONCLUSION: No significant differences were found between patients with the primary mutation to zidovudine and control patients harbouring wild-type virus in terms of short-term response measured by serum viral load and CD4+ cell counts.

Adult↗