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PubMed2004

Feline immunodeficiency virus: a concise review.

Among non-primate vertebrates, feline immunodeficiency virus (FIV) infection in the cat may be the closest model of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Clinical evolution and immunological and virological relationships between human HIV/AIDS and disease produced by FIV infection in cats are very close. These similarities should facilitate progress in the understanding of mechanisms of viral infection and immunopathology, and make this model potentially very valuable in evaluation of experimental therapeutic approaches to AIDS in man. Development of feline immunodeficiency virus vectors bearing therapeutic genes targeting different human diseases is a promising strategy for gene therapy, despite some recent studies which suggest that despite lack of evidence of infection of man by FIV, additional epidemiological surveillance may be indicated to determine if transmission can occur from this close companion to humans in some circumstances.

Animals↗

PubMed2002

Infection of macaques with a molecular clone, SHIVSF33A2, provides evidence for tissue specific variants.

Infection of rhesus macaques with chimeric simian-human immunodeficiency viruses (SHIV) is an established model to study acquired immunodeficiency syndrome (AIDS) pathogenesis. Such a controlled system allows for detailed analysis of the molecular determinants of viral pathogenesis in addition to studying host-specific immune responses that modulate disease progression. Furthermore, the use of a pathogenic molecular clone affords the opportunity to study both viral evolution within a host and to examine the generation of tissue specific variants. In this report we describe viral diversification within tissues of two rhesus macaques infected intravenously with the CXCR4-specific molecular clone SHIVSF33A2. Heteroduplex tracking analysis (HTA) was used to determine the complexity of viral DNA within distinct lymphoid tissues. Not surprising, heterogeneity of the proviral quasispecies in tissues obtained during the acute infection was limited. However, tissues obtained at necropsy harbored a more diverse and often different population of env variants. As the inoculating virus is a molecular clone, the variants generated are likely due to the presence of tissue specific selective forces rather than a founder's effect.

Animals↗

PubMedDate not supplied

[Crusted scabies (Norwegian scabies) a case report].

Different types of scabies have been described based on their clinical outcome, one of which is the Crusted (Norwegian) type. This is an extreme manifestation of scabies that can be observed mainly among immunosupressed patients. A case ofa 42 year-old homosexual man is described. The patient was diagnosed with HIV, presenting pruritic lesions with a 4 month evolution in trunk and extremities. Lesions included xerosis, decapitated papules, badges with erythema, residual hyperchromic stains, multiple abrasions and ungueal pigmentation in both feet. At the beginning it was treated as apsorasiform dermatitis with steroids and antipruritics without success. Through a biopsy the suspected diagnosis of Crusted (Norwegian) scabies was confirmed. The patient was treated with a dose of oral ivermectin and topical benzyl benzoate and showed remission after two days.

Acquired Immunodeficiency Syndrome↗

PubMed1987

[Stomatological lesions seen in HIV virus infection. II. Histopathological and ultrastructural studies].

Buccal lesions observed in the clinical setting of human immunodeficiency virus (HIV) infection constitute a diverse group of pathological entities. Several are related to the opportunistic infections observed in association with HIV infection. "Hairy leukoplakia" is a recently described benign lesion that is presumably related to infection by Epstein-Barr virus (E.B.V.). Kaposi's sarcoma is seen somewhat frequently in the oral cavity, especially involving the palate of HIV infected patients. We have observed this lesion 19 times in this location. The diagnosis is usually relatively straight-forward. Both vascular inflammatory and more typical sarcomatous morphology sub-types are present. The salivary glands may show an important lymphoplasmocytic infiltration which is unusual in that associated epithelial changes are not observed. The salivary glands seem to be a seat of the lymphocytic infiltration seen in other organs during the course of HIV infection. As for the changes encountered in the lymph nodes in HIV infection, they represent different stages in the evolution of a dynamic process, which progresses from hyperplasia to atrophy of the lymph nodes.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Drug interactions between psychoactive substances and antiretroviral therapy in individuals infected with human immunodeficiency and hepatitis viruses.

The liver disease characteristic of alcohol dependence encompasses three main related entities: steatosis, alcoholic hepatitis, and cirrhosis. Alcoholic cirrhosis is a leading cause of global morbidity and mortality. Alcohol intake among injecting drug users is a major contributor to transmission of viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C viruses (HCV). HIV and HCV coinfected patients develop liver diseases earlier and more severely than the monoinfected individuals, including hepatocellular carcinoma. Interactions exist between the therapeutic drugs used to minimize and control the drug and alcohol dependence. Furthermore, drug-drug interactions occur between the highly active antiretroviral therapy (HAART) and alcohol, different HAART components and methadone, or each one of the therapies with the other, thus contributing to a higher toxicity level. With the evolution of effective antiretroviral therapy, survival of persons with HIV, and the syndrome it causes, acquired immunodeficiency syndrome (AIDS) has increased dramatically. Drug-drug interactions may appear between alcohol and anti-HBV or anti-HCV, therapy in the presence or absence of anti-HIV therapy. Several other medical-, social-, and drug-related factors of this population have to be considered when providing HAART. Because many coinfected patients also have problems with substance use, dealing with their drug dependence is an important first step in an attempt to improve adherence to and tolerance of antiviral therapy. It is necessary to minimize the risk of liver disease acceleration and/or reinfection with hepatitis viruses. Knowledge of potential drug interactions between methadone, antiretroviral therapy, psychoactive drugs, and antipsychotics and the role of coinfection with HBV or HCV and the drugs used in eradicating viral hepatitis permits suitable antiretroviral combinations.

Alcoholism↗

PubMed1997

Evolution of human immunodeficiency virus subtype A in women seroconverting post partum and in their offspring post-natally infected by ingestion of breast milk.

The evolution of genomic RNA of human immunodeficiency virus type 1 (HIV-1), subtype A, was studied in three Rwandan mother-child pairs over a period of 12-30 months. In two pairs a homogeneous subtype A V3 sequence population was observed at seroconversion and the virus populations in the children resembled those in the mothers. One of these mother-child pairs was infected with an A/C recombinant virus (Ap17/Cp24). In the third pair, a heterogeneous V3 sequence population was observed in the maternal seroconversion sample but the V3 sequence population in the child's sample was homogeneous. In each individual the intra- and intersample variation (between the seroconversion and follow-up samples) increased over time in both the V3 region and p17gag. Independent evolution for 1-2 years did not abolish the epidemiological relationship between virus populations in mother and child.

Amino Acid Sequence↗

PubMed1994

Estimating patterns of CD4 lymphocyte decline using data from a prevalent cohort of HIV infected individuals.

In natural history studies of chronic disease, it is of interest to understand the evolution of key variables that measure aspects of disease progression. This is particularly true for immunological variables among persons infected with the human immunodeficiency virus (HIV). The natural time scale for such studies is time since infection. Most data available for analysis, however, arise from prevalent cohorts, where the date of infection is unknown for most or all individuals. As a result, standard curve fitting algorithms are not immediately applicable. Here we propose two methods to circumvent this difficulty. The first uses repeated measurement data to provide information not only on the level of the variable of interest, but also on its rate of change, and is based on the principal curves algorithm of Hastie and Stuetzle. The second uses an external estimate of the expected time since infection. Both methods use locally-weighted linear smoothers, and are applied to data from a prevalent cohort of HIV-infected homosexual men, giving estimates of the average pattern of CD4 lymphocyte decline. These methods apply to natural history studies that use data from prevalent cohorts where the time of disease origin is uncertain, provided availability of certain information from external sources.

Algorithms↗

PubMed1991

Discontinuous sequence change of human immunodeficiency virus (HIV) type 1 env sequences in plasma viral and lymphocyte-associated proviral populations in vivo: implications for models of HIV pathogenesis.

Sequence change in different hypervariable regions of the external membrane glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1) was studied. Viral RNA associated with cell-free virus particles circulating in plasma and proviral DNA present in HIV-infected peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of two currently asymptomatic hemophiliac patients over a 5-year period. HIV sequences were amplified by polymerase chain reaction to allow analysis in the V3, V4, and V5 hypervariable regions of gp120. Rapid sequence change, consisting of regular replacements by a succession of distinct viral populations, was found in both plasma virus and PBMC provirus populations. Significant differences between the frequencies of sequence variants in DNA and RNA populations within the same sample were observed, indicating that at any one time point, the predominant plasma virus variants were antigenically distinct from viruses encoded by HIV DNA sequences in PBMCs. How these findings contribute to current models of HIV pathogenesis is discussed.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Convergent evolution of reverse transcriptase (RT) genes of human immunodeficiency virus type 1 subtypes E and B following nucleoside analogue RT inhibitor therapies.

Changes in the drug susceptibility, gene lineage, and deduced amino acid sequences of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) subtype E following 3'-azido-3'-deoxythymidine (AZT) monotherapy or AZT-2', 3'-dideoxyinosine combination therapy were examined with sequential virus isolates from a single family. The changes were compared to those reported for HIV-1 subtype B, revealing striking similarities in selected phenotype and amino acids independent of differences in the RT backbone sequences that constantly distinguish the two subtypes. Particularly, identical amino acid substitutions were present simultaneously at four different positions (D67N, K70R, T215F, and K219Q) for high-level AZT resistance. These data suggest that HIV-1 subtypes E and B evolve convergently at the phenotypic and amino acid levels when the nucleoside analogue RT inhibitors act as selective forces.

Amino Acid Sequence↗

PubMed2003

Time-updated CD4+ T lymphocyte count and HIV RNA as major markers of disease progression in naive HIV-1-infected patients treated with a highly active antiretroviral therapy: the Aquitaine cohort, 1996-2001.

In naive HIV-1 infected patients who start a highly active antiretroviral therapy (HAART), the relationship between time-updated CD4+ cell count, HIV RNA, and clinical progression (new AIDS-defining event or death) is incompletely understood. A 2-step statistical approach was adopted: first, modeling the evolution of the 2 markers taking into account left-censoring of HIV RNA and, second, studying their respective effect on clinical progression. The study sample consisted in 551 previously untreated patients of the Aquitaine Cohort who started their first HAART regimen between 1996 and 2000. During a median follow-up of 33 months, 46 patients experienced a new AIDS-defining diagnosis and 23 died. In multivariate survival analysis, time-updated CD4+ cell count (hazard ratio [HR] = 1.92 for 100 cells/mm3 lower, P < 10(-4) and HIV RNA (HR = 1.30 for 1 log(10) copies/mL higher, P = 0.04) on continuous scale were associated with clinical progression. When analyzing the effect of updated biomarkers using usual thresholds, the association with clinical progression was weaker for CD4+ but still significant (P = 0.007) whereas it remained only significant for updated HIV RNA above 4 log(10) copies/mL (P = 0.01). The prognostic information of updated HIV RNA adjusted on updated CD4+ is significant but depends on how the markers are taken into account. Clinical decisions and interpretation of clinical trial results must weigh the signification of each of these 2 biomarkers.

Adult↗

PubMed1996

Anti-CD4 therapy for AIDS suggested by mathematical models.

HIV-1 infection typically involves a long clinical latency stage during which CD4 counts decline slowly. For the later part of the clinical latency stage it was found recently that this is a highly dynamic phase characterized by rapid turnover rates. Clinical latency can therefore be considered as a quasi-equilibrium state in which CD4 and HIV-1 turnover are in almost perfect balance. Here we consider this quasi-equilibrium to be the stable steady state of a simple host-parasite model in which the parasite (HIV-1) level is determined by the availability of infectable hosts (activated CD4+ T cells). Such models adequately account for the clinical data on the evolution of drug resistant mutants appearing after the administration of anti-HIV drugs. The model suggests a novel therapeutic approach for AIDS: reducing the CD4 count slightly will strongly reduce the HIV load. Combining this anti-CD4 treatment with conventional anti-HIV therapy would prevent the outgrowth of drug resistant mutants.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Directed evolution of retrovirus envelope protein cytoplasmic tails guided by functional incorporation into lentivirus particles.

In contrast to most gammaretrovirus envelope proteins (Env), the Gibbon ape leukemia virus (GaLV) Env protein does not mediate the infectivity of human immunodeficiency virus type 1 (HIV-1) particles. We made use of this observation to set up a directed evolution system by creating a library of GaLV Env variants diversified at three critical amino acids, all located around the R-peptide cleavage site within the cytoplasmic tail. This library was screened for variants that were able to functionally pseudotype HIV-1 vector particles. All selected Env variants mediated the infectivity of HIV-1 vector particles and encoded novel cytoplasmic tail motifs. They were efficiently incorporated into HIV particles, and the R peptide was processed by the HIV protease. Interestingly, in some of the selected variants, the R-peptide cleavage site had shifted closer to the C terminus. These data demonstrate a valuable approach for the engineering of chimeric viruses and vector particles.

Amino Acid Sequence↗

PubMed2004

Rapid evolution of primate antiviral enzyme APOBEC3G.

Human cytidine deaminase APOBEC3G and the virion infectivity factor (vif) of the human immunodeficiency virus (HIV) are a pair of antagonistic molecules. In the absence of vif, APOBEC3G induces a high rate of dC to dU mutations in the nascent reverse transcripts of HIV that leads to the degradation of the HIV genome. HIV vif, on the other hand, can suppress the translation and trigger the degradation of human APOBEC3G. Here, we studied the rate of APOBEC3G gene evolution from five hominoids and two Old World monkeys. Averaged across the entire coding region, the rate of non-synonymous nucleotide substitutions is approximately 1.4 times the rate of synonymous substitutions, strongly suggesting that APOBEC3G has been under positive Darwinian selection. A comparison between the nucleotide polymorphisms within humans and the substitutions among the seven primates reveals a significant excess of non-synonymous substitutions. Furthermore, the rate of charge-altering non-synonymous substitution is approximately 1.8 times that of charge-conserving substitution, indicating that the selection is promoting the diversity of the protein charge profile. However, no difference in selective pressure on APOBEC3G is detected between hosts and non-hosts of HIV or simian immunodeficiency virus (SIV). These results, together with recent findings that the antiviral activity of APOBEC3G is not limited to HIV/SIV, suggest that the selective pressure on APOBEC3G is not solely from HIV/SIV and that APOBEC3G is a broad antiviral enzyme. The identification of pervasive positive selection for charge-altering amino acid substitutions supports the hypothesis of electrostatic interactions between APOBEC3G and vif or its functional equivalents.

APOBEC-3G Deaminase↗

PubMed2003

Dual pressure from antiretroviral therapy and cell-mediated immune response on the human immunodeficiency virus type 1 protease gene.

Human immunodeficiency virus (HIV)-specific CD8(+) T-lymphocyte pressure can lead to the development of viral escape mutants, with consequent loss of immune control. Antiretroviral drugs also exert selection pressures on HIV, leading to the emergence of drug resistance mutations and increased levels of viral replication. We have determined a minimal epitope of HIV protease, amino acids 76 to 84, towards which a CD8(+) T-lymphocyte response is directed. This epitope, which is HLA-A2 restricted, includes two amino acids that commonly mutate (V82A and I84V) in the face of protease inhibitor therapy. Among 29 HIV-infected patients who were treated with protease inhibitors and who had developed resistance to these drugs, we show that the wild-type PR82V(76-84) epitope is commonly recognized by cytotoxic T lymphocytes (CTL) in HLA-A2-positive patients and that the CTL directed to this epitope are of high avidity. In contrast, the mutant PR82A(76-84) epitope is generally not recognized by wild-type-specific CTL, or when recognized it is of low to moderate avidity, suggesting that the protease inhibitor-selected V82A mutation acts both as a CTL and protease inhibitor escape mutant. Paradoxically, the absence of a mutation at position 82 was associated with the presence of a high-avidity CD8(+) T-cell response to the wild-type virus sequence. Our results indicate that both HIV type 1-specific CD8(+) T cells and antiretroviral drugs provide complex pressures on the same amino acid sequence of the HIV protease gene and, thus, can influence viral sequence evolution.

Antiretroviral Therapy, Highly Active↗

PubMed2005

Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients are more predisposed than HIV-negative women to develop squamous intraepithelial lesions (SIL) of the uterine cervix, and cervical dysplasia may be of higher grade in HIV-positive women than in HIV-negative subjects, with more extensive and multi-centric involvement of the lower genital tract by human papillomavirus (HPV)-associated lesions. Moreover, recurrence and progression rate of cervical intraepithelial neoplasia (CIN) is particularly higher in immunocompromised women. DESIGN: Retrospective case-control study of HIV-positive women and HIV-negative controls, all affected by low-grade SIL of the uterine cervix, treated by loop excision or followed-up without treatment. Correlation of progression and recurrence of SIL with HIV status and CD4+ count. PATIENTS: From September 1990 to October 1997, 75 HIV-positive low-grade-SIL patients, 47 treated and 28 followed-up without treatment, and 75 HIV-negative low-grade-SIL controls, 45 treated and 30 followed-up. RESULTS: Among treated patients, 17/47 (36.2%) HIV-positive and 5/45 (11.1%) controls had recurrence (P < 0.0101, O.R. = 4.53, 95% CI = 1.5-13.7), progression of untreated lesion was seen in 15/28 (53.6%) HIV-positive and 7/30 (23%) controls (P < 0.05, O.R. = 3.79, 95% CI = 1.23-11.69). The risk of recurrence or progression of low-grade SIL linked to HIV seropositivity is about 4-5 times higher in comparison with seronegative counterpart, matched for age, risk factors and lesion size. More significantly, considering the cut-off of 200 CD4+/mm(3) in HIV-positive women, 13/17 cases of recurrence (P < 0.05, O.R. = 4.88, 95% CI = 1.28-18.58) and 10/15 cases with progression (P < 0.05, O.R. = 6.67, 95% CI = 1.24-35.73) were immunocompromised (<200 CD4+/mm3), with a significant higher risk of recurrence or progression linked to immunodeficiency status. Considering time of progression or recurrence, during follow-up, Kaplan-Meier curves shows that HIV-positive status and immunodeficiency are correlated with more rapid evolution of cervical dysplasia and HPV-related lesions: comparison of recurrence in treated patients report P < 0.005 and progression in untreated P<0.05 (Mantel-Haenszel log-rank test). CONCLUSIONS: Immunological status seems to be a determinant factor in prognosis of cervical SIL, HIV-positive women affected by this lesion, even if low-grade, need more aggressive management than the immunocompetent counterpart. Strict cytologic and colposcopic screening is recommended and CD4+ count and HPV-DNA testing may be useful risk indicators. Excisional procedures are preferred, while ablative treatments or wait and see policy may expose to some risk this type of population with poor compliance to follow-up.

Case-Control Studies↗

PubMed2002

Analysis of the immune response and viral evolution during the acute phase of SIV infection.

Development of an effective vaccine against human immunodeficiency virus (HIV) will require knowledge of the immune responses that correlate with protection. During the acute phase of HIV infection the host immune responses appear to control viral replication. It is thought that virus-specific cellular immunity is intimately involved in this viral control. We have developed a model system to measure the entire T cell response and viral evolution in the face of this onslaught in rhesus macaques during the acute phase of infection with molecularly cloned simian immunodeficiency virus (SIV). We used intracellular cytokine staining (ICS) of peripheral blood mononuclear cells (PBMCs) from animals during the acute phase of viral infection stimulated with peptides spanning the entire protein sequence of SIV to determine which peptides were recognized by CD8 and CD4 positive T cells. Furthermore, we sequenced the entire virus during the acute phase of infection. This approach has proved highly effective for measuring acute phase T cell responses and viral evolution in SIV-infected rhesus macaques and might facilitate the definition of cellular immune responses in HIV-infected humans during the acute phase.

Acute Disease↗

PubMed2005

Diversity, divergence, and evolution of cell-free human immunodeficiency virus type 1 in vaginal secretions and blood of chronically infected women: associations with immune status.

Most human immunodeficiency virus type 1 (HIV-1) infections are believed to be the result of exposure to the virus in genital secretions. However, prevention and therapeutic strategies are usually based on characterizations of HIV-1 in blood. To understand better the dynamics between HIV-1 quasispecies in the genital tract and blood, we performed heteroduplex assays on amplified env products from cell-free viral RNA in paired vaginal secretion (VS) and blood plasma (BP) samples of 14 women followed for 1.5 to 3.5 years. Diversity and divergence were less in VS than in BP (P = 0.03 and P < 0.01, respectively), and divergence at both sites was correlated with blood CD4(+) cell levels (VS, P = 0.05; BP, P = 0.01). Evolution of quasispecies was observed in 58% of the women; the loss or gain of quasispecies in VS or BP was always accompanied by such changes at the other site. In addition, sustained compartmentalization of quasispecies in VS was found for four women, even as CD4(+) cell levels decreased to low levels (<50 cells/microl). Quasispecies changes over time were associated with fluctuations in CD4(+) cell levels; concordant increases or decreases in VS and BP divergence had greater CD4(+) cell level changes than intervals with discordant changes (P = 0.05), and women with evolving quasispecies had greater decreases in CD4(+) cell levels compared to that for women who maintained the same quasispecies (P < 0.05). Thus, diversity, divergence, and evolution of cell-free HIV-1 in VS can be different from that in BP, and dynamics between their respective quasispecies are associated with changes in CD4(+) cell levels.

Adolescent↗

PubMed1998

A prophylactic and therapeutic AIDS vaccine containing as a component the innocuous Tat toxoid.

Extracellular Tat can act as a viral toxin on uninfected cells of different tissues, including the CNS and the immune system, thus in order to immunize humans against Tat we have prepared a biologically inactivated but immunogenic Tat (Tat Toxoid). Tat Toxoid is not toxic in mice even at high doses. It triggers high levels of specific Tat Abs in the mouse and rabbit. Furthermore, in humans Tat Toxoid immunization was safe and induced in seronegatives persistent high levels of Tat Abs and in immunodeficient patients a significant rise of these specific Abs. Facing acute HIV-1 infection, the presence of high level of circulating Tat Abs promoted by Tat Toxoid vaccine should prevent Tat-induced immunosuppression and allow anti-HIV-1 cellular response to develop. As a consequence, early release of beta-chemokines could enhance host resistance towards HIV-1, and, in infected people, inhibit viral replication and evolution towards AIDS.

AIDS Vaccines↗