Progression Of Human Immunodeficiency Virus Type Research Articles

Association of TREX1 polymorphism with disease progression in human immunodeficiency virus type-1 (HIV-1) infected patients.

The time interval between HIV-1 infection and AIDS development is not the same in all patients and depends largely on the genetic background of the individual. Polymorphisms in the TREX1 gene, the main enzyme in the clearance of cytosolic DNA, affect type 1 interferon-mediated inflammatory response in HIV-1 infection. We aimed to study the role of a single nucleotide polymorphism (rs3135941) of the TREX1 gene and the rate of disease progression in patients infected with HIV-1. A total of 190 HIV-1 infected patients were recruited. Patients' demographic and laboratory data including CD4 counts, viral load, and antiretroviral therapy (ART) were collected. The genotype of rs3135941 was determined by a PCR-SSP method. The rate of progression to AIDS was calculated with Kaplan-Meier survival analysis using Stata software. The patients were divided into rapid and slow progressors based on time interval of CD4 drop below 350/µl. Kaplan-Meier analysis revealed an accelerated disease progression in patients with TC and CC genotypes (HR = 1.49, 95% CI = 1.01-2.17). The mean values of the first 5-year CD4 counts were significantly different in patients who had CC and TC genotypes compared to the TT group (p = 0.036). The result of this study emphasizes the importance of TREX1 polymorphism in HIV-1 progression. These data warrant further investigation into the role of other polymorphisms of TREX1.

Stability of HIV-1 Dynamics Models with Viral and Cellular Infections in the Presence of Macrophages

In this research work, we suggest two mathematical models that take into account (i) two categories of target cells, CD4+T cells and macrophages, and (ii) two modes of infection transmissions, the direct virus-to-cell (VTC) method and cell-to-cell (CTC) infection transmission, where CTC is an effective method of spreading human immunodeficiency virus type-1 (HIV-1), as with the VTC method. The second model incorporates four time delays. In both models, the presence of a bounded and positive solution of the biological model is investigated. The existence conditions of all equilibria are established. The basic reproduction number R0 that identifies a disease index is obtained. Lyapunov functions are utilized to verify the global stability of all equilibria. The theoretical findings are verified through numerical simulations. According to the outcomes, the trajectories of the solutions approach the infection-free equilibrium and infection-present equilibrium when R0≤1 and R0>1, respectively. Further, we study the sensitivity analysis to investigate how the values of all the parameters of the suggested model affect R0 for given data. We discuss the impact of the time delay on HIV-1 progression. We find that a longer time delay results in suppression of the HIV-1 infection and vice versa.

Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors.

The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and its expression correlates with more profound pathogenicity, rapid progression to acquired immunodeficiency syndrome (AIDS), and greater AIDS-related mortality. There is still no cure for AIDS and no method for preventing or eradicating HIV-1 infection. HIV-1 entry begins with the interaction of the viral envelope glycoprotein gp120 and the primary receptor CD4, and subsequently with the coreceptors, CCR5 or CXCR4, on the host cells. Blocking the interaction of HIV-1 and its coreceptors is therefore a promising strategy for developing new HIV-1 entry inhibitors. This approach has a dual benefit, as it prevents HIV-1 infection and progression while also targeting the reservoirs of HIV-1 infected, coreceptor positive macrophages and memory T cells. To date, multiple classes of CXCR4-targeted anti-HIV-1 inhibitors have been discovered and are now at different preclinical and clinical stages. In this review, we highlight the studies of CXCR4-targeted small-molecule and peptide HIV-1 entry inhibitors discovered during the last two decades and provide a reference for further potential HIV-1 exploration in the future. Impact statement This minireview summarized the current progress in the identification of CXCR4-targeted HIV-1-entry inhibitors based on discovery/developmental approaches. It also provided a discussion of the inhibitor structural features, antiviral activities, and pharmacological properties. Unlike other reviews on anti-HIV-1 drug development, which have generally emphasized inhibitors that target intracellular viral replication and host genomic integration, this review focused on the drug discovery approaches taken to develop viral-entry inhibitors aimed at disturbing the initial step of viral interaction with uninfected host cells and preventing the subsequent viral replication/genomic integration. This review amalgamated recently published and important work on bivalent CXCR4-targeted anti-HIV-1-entry candidates/conjugates, discussed the research challenges faced in developing drugs to prevent and eradicate HIV-1 infection, and provided a perspective on strategies that can lead to future drug discoveries. The findings and strategies summarized in this review will be of interest to investigators throughout the microbiological, pharmaceutical, and translational research communities.

Histoarchitectural Deterioration of Lymphoid Tissues in HIV-1 Infection and in Aging.

Impaired immunity is a common symptom of aging and advanced Human Immunodeficiency Virus type 1 (HIV-1) disease. In both diseases, a decline in lymphocytic function and cellularity leads to ineffective adaptive immune responses to opportunistic infections and vaccinations. Furthermore, despite sustained myeloid cellularity there is a background of chronic immune activation and a decrease in innate immune function in aging. In HIV-1 disease, myeloid cellularity is often more skewed than in normal aging, but similar chronic activation and innate immune dysfunction typically arise. Similarities between aging and HIV-1 infection have led to several investigations into HIV-1-mediated aging of the immune system. In this article, we review various studies that report alterations of leukocyte number and function during aging, and compare those alterations with those observed during progressive HIV-1 disease. We pay particular attention to changes within lymphoid tissue microenvironments and how histoarchitectural changes seen in these two diseases affect immunity. As we review various immune compartments including peripheral blood as well as primary and secondary lymphoid organs, common themes arise that help explain the decline of immunity in the elderly and in HIV-1-infected individuals with advanced disease. In both conditions, lymphoid tissues often show signs of histoarchitectural deterioration through fat accumulation and/or fibrosis. These structural changes can be attributed to a loss of communication between leukocytes and the surrounding stromal cells that produce the extracellular matrix components and growth factors necessary for cell migration, cell proliferation, and lymphoid tissue function. Despite the common general impairment of immunity in aging and HIV-1 progression, deterioration of immunity is caused by distinct mechanisms at the cellular and tissue levels in these two diseases.

Lower High-Density Lipoproteins Levels During Human Immunodeficiency Virus Type 1 Infection Are Associated With Increased Inflammatory Markers and Disease Progression.

High-density lipoproteins (HDL) are responsible for the efflux and transport of cholesterol from peripheral tissues to the liver. In addition, HDL can modulate various immunological mechanisms, including the inflammatory response. Inflammasomes are multiprotein complexes that have been reported to be activated during human immunodeficiency virus type 1 (HIV-1) infection, thus contributing to immune hyperactivation, which is the main pathogenic mechanism of HIV-1 progression. However, the relationship between HDL and inflammasomes in the context of HIV-1 infection is unclear. Therefore, this research aims to explore the association between HDL and the components of the inflammatory response during HIV-1 infection. A cross-sectional study, including 36 HIV-1-infected individuals without antiretroviral treatment and 36 healthy controls matched by sex and age, was conducted. Viral load, CD4+ T-cell counts, serum HDL, and C-reactive protein (CRP) were quantified. Serum cytokine levels, including IL-1β, IL-6, and IL-18, were assessed by ELISA. The inflammasome-related genes in peripheral blood mononuclear cells were determined by quantitative real-time PCR. HIV-1-infected individuals showed a significant decrease in HDL levels, particularly those subjects with higher viral load and lower CD4+ T-cell counts. Moreover, upregulation of inflammasome-related genes (NLRP3, AIM2, ASC, IL-1β, and IL-18) was observed, notably in those HIV-1-infected individuals with higher viral loads (above 5,000 copies/mL). Serum levels of IL-6 and CRP were also elevated in HIV-1-infected individuals. Significant negative correlations between HDL and the mRNA of NLRP3, AIM2, ASC, IL-1β, and IL-18, as well as viral load and CRP were observed in HIV-1-infected individuals. Likewise, a significant positive correlation between HDL and CD4+ T-cell counts was found. In summary, our results indicate that HDL might modulate the expression of several key components of the inflammasomes during HIV-1 infection, suggesting a novel role of HDL in modifying the inflammatory state and consequently, the progression of HIV-1 infection.

Protective Role of BST2 Polymorphisms in Mother-to-Child Transmission of HIV-1 and Adult AIDS Progression.

Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.

Profound Immune Exhaustion and Downregulation Of Interleukin-7 Alpha Receptor (CD127) In CD8 and CD4 T-Cell Subsets In Jamaican Patients Co-Infected With Human T-Cell Lymphotropic Virus Type-1 and Human Immunodeficiency Virus Type-1 Despite Normal Or Above Normal CD4 Counts

BackgroundNext to Sub-Saharan Africa, the Caribbean has the second highest prevalence of human immunodeficiency virus type 1 (HIV-1) infection; and human T-cell lymphotropic virus type 1 (HTLV-1), another human retrovirus, is also endemic. Fewer than five percent of persons with HTLV-1, predominantly transmitted through breast feeding, progress to any of the myriad associated diseases, including adult T-cell leukemia, HTLV-1 associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP), or polymyositis. HTLV-1, through its oncoprotein-like transactivating (Tax) protein, results in aberrant proliferation of CD4 cells through interaction with cell cycle regulators, and activation of nuclear factor kappa B and the interleukin-2 pathway. Elevated CD4 counts, often above normal range, observed in patients with HTLV-1/HIV-1 co-infection, may be spurious, posing a challenge for laboratory monitoring of lymphoproliferative disorders or HIV-1 progression. MethodsWe compared CD4 counts, HIV-1 viral load, and clinical parameters in a cohort of patients co-infected with HTLV-1 and HIV-1 (syphilis, hepatitis B and C non-reactive), with controls with HIV-1 infection only matched for age, sex, and duration of antiretroviral therapy, as well as donors without HTLV-1 or HIV-1 infection. We used flow cytometry to characterize CD4 and CD8 naïve and memory T-cell subsets, expression of T-cell survival and homeostatic cytokine interleukin-7 alpha receptor (CD127), and examined the role of co-inhibitory programmed death-1 in HTLV-1 infected (intracellular HTLV-1 Tax protein-expressing) and HIV-1 infected (intracellular HIV-1 Gag protein-expressing) CD4 cells in immune evasion. Additionally, we assessed the effects of exogenous interleukin-7 (IL-7) and programmed death-1 pathway blockade on the function of responding CD8 cytotoxic T-lymphocyte (CTL) subsets ex vivo. ResultsAll patients with HTLV-1 and HIV-1 co-infection (n = 5) were female and of median age 42 years (range, 22 to 49 years), with normal or above normal CD4 counts. Four of five patients with HTLV-1/HIV-1 co-infection were WHO Stage 4 HIV/AIDS at diagnosis (e.g., oesophageal candidiasis, HIV nephropathy). Median duration since diagnosis with HIV-1 infection was six years (range, 1 to 18 years), and unexpectedly high CD4 count was the reason for HTLV-1/2 testing in all cases. Nadir CD4 count among patients with HTLV-1/HIV-1 co-infection was significantly higher than controls with HIV-1 infection only (n = 12) matched for age, sex, and duration of antiretroviral therapy (median 684, range 467 to 1474; and median 36, range, 8 to 352 cells per microliter, respectively; p = 0.007, Mann-Whitney U test). Flow cytometric analyses of CD8 and CD4 T-cell memory subsets revealed more profound loss of CD127 in the CD8 compared to the CD4 compartment; and CD8(+) effector memory T-cells showed the most significant downregulation of CD127 when patients with HTLV-1/HIV-1 co-infection were compared with seronegative donors (40.3±17.0%, n =5; and 73.1±7.48%, n = 10, respectively; p = 0.032, Mann-Whitney U). In ex vivo experiments in the context of peripheral blood mononuclear cells, preliminary data suggest that patients with HTLV-1/HIV-1 co-infection have impaired CD8(+) CTL function in response to HLA-restricted HTLV-1 Tax11-19 and cytomegalovirus (CMV) pp65 peptide stimulation. Further, we sought to describe expression of co-inhibitory marker programmed death-1 ligand (PDL1) on intracellular HTLV-1 Tax protein- as well as intracellular HIV-1 Gag protein-expressing CD4 cells. Blockade of PDL1 resulted in partial recovery of CTL function in patients with HTLV-1/HIV co-infection, and enhanced killing of target cells infected with either HTLV-1 or HIV-1. ConclusionsPatients with HTLV-1/HIV-1 co-infection show profound CTL exhaustion; and CD4 cells, although within or above normal CD4 count range, show aberrant naïve and memory T-cell distribution and possible immune evasion by upregulation of the programmed death-1 pathway, blockade of which showed a tendency towards enhanced virus-specific CTL function and killing of target cells infected with HTLV-1 or HIV-1. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Phase I Randomized Clinical Trial of Candidate Human Immunodeficiency Virus type 1 Vaccine MVA.HIVA Administered to Gambian Infants

BackgroundA vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.Trial DesignWe conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.MethodsInfants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.ResultsFrom March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.ConclusionsA single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group.Trial RegistrationClinicalTrials.gov NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116

The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans

Populations of African ancestry continue to account for a disproportionate burden of the human immunodeficiency virus type 1 (HIV-1) epidemic in the United States. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in 2 cohorts: Reaching for Excellence in Adolescent Care and Health (REACH) and HIV Epidemiology Research Study (HERS). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T cells were examined both separately and combined to represent 3 categories of HIV-1 disease control (76 controllers, 169 intermediates, and 93 noncontrollers). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with 1 or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and nongenetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection cross the boundaries of race and viral subtype, whereas others appear confined within one or the other of those boundaries.

APOBEC3B deletion and risk of HIV-1 acquisition.

The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from 5 human immunodeficiency virus type 1 (HIV-1) natural history cohorts. The hemizygous genotype had no effect on either acquisition of HIV-1 infection or progression to AIDS. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (odds ratio, 7.37; P= .024), progression to AIDS (relative hazard, 4.01; P=. 03), and viral set point (P= .04). These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1 acquisition and progression to AIDS and warrant further study.

The role of infant immune responses and genetic factors in preventing HIV-1 acquisition and disease progression.

Mother-to-child HIV-1 transmission accounts for more than 700 000 new paediatric HIV-1 infections in developing countries each year [1]. This comprises less than one-third of the infants born to human immunodeficiency virus type 1 (HIV-1) infected mothers, the majority of whom remain uninfected despite recurrent risk for contact with the virus in utero, during delivery and through breastfeeding. A comprehensive approach to studying infant immunity against HIV-1 may provide insight into the determinants of HIV-1 acquisition, promote an understanding of resistance to infection in the setting of repeated exposure to the virus and contribute to the development of therapeutic interventions or vaccines against HIV-1 transmission. Several unique features of mother-to-child HIV-1 transmission provide advantages in determining correlates of HIV-1 acquisition and viral immunity when compared to sexual HIV-1 transmission models. Both HIV-1 infected mothers and their exposed infants can be evaluated for viral and immunological factors associated with transmission. HIV-1 exposure can be characterized by quantifying maternal HIV-1 viral load in plasma, breast milk and genital tract secretions, and infant immune responses can be defined simultaneously or near the time of exposure. Timing of transmission can be estimated using HIV-1 polymerase chain reaction (PCR) at birth and at regular intervals after exposure during delivery and breastfeeding. Vertical HIV-1 transmission risk is also higher than sexual transmission risk. Per sexual act, it is estimated that the risk of heterosexual transmission is approximately 0·1% in an antiretroviral naive population [2]. The risk of HIV-1 acquisition during delivery ranges from 10 to 20%, more than 100-fold higher than heterosexual transmission rates. Disparities between heterosexual and vertical HIV-1 transmission rates persist in the setting of antiretroviral therapy. This enables mother–child transmission studies to provide robust epidemiological data regarding specific immune mechanisms and combinations of immune responses that may constitute protective immunity against HIV-1. This review examines the spectrum of innate, humoral and cellular immune responses and genetic factors that have been studied in infants who are HIV-1 infected or HIV-1 exposed and uninfected (Fig. 1). Fig. 1 Immune responses and genetic factors associated with mother-to-child HIV-1 transmission and paediatric HIV-1 disease progression. *May be maternally acquired in utero or via breast milk. †Alloimmunity is dependent on degree of maternal–infant ... INNATE IMMUNITY Innate immune responses are generated rapidly and are important in preventing and containing infections with a variety of viral pathogens. Broad innate immunity may also be capable of protecting against immune-escape viruses generated by more narrow adaptive immune responses. In HIV-1 transmission and disease progression, relevant innate mechanisms of immunity include the activity of natural killer (NK) cells and antiviral proteins such as the CC chemokines, CD8+ antiviral factor (CAF) and secretory leucocyte protease inhibitor (SLPI). Natural killer (NK) cell activity Natural killer (NK) cells induce inflammation and lyse infected cells without prior sensitization and in a non-HLA restricted manner. NK cells from HIV-1 infected individuals release the CC chemokines MIP-1α, MIP-1β and RANTES, three factors that have been shown to inhibit HIV-1 independently in vitro by blocking the CCR5 HIV-1 coreceptor [3,4]. NK cells also act by lysing HIV-1 infected cells via antibody-dependent cellular cytotoxicity (ADCC). This is initiated by binding of NK cell Fc receptors (CD16) to target cells coated with HIV-specific antibodies of the subclass IgG1 [5–7]. HIV-specific ADCC antibodies are directed against the viral envelope glycoproteins gp120 and gp41 and are distinct from virus-neutralizing antibodies [8]. There is conflicting evidence regarding the role of NK cells in containing HIV-1 in chronically infected children and in preventing vertical HIV-1 transmission. Several studies have evaluated HIV-specific ADCC antibody titres in sera of infants born to HIV-1 infected mothers and found that these antibodies are transferred efficiently across the placenta from mother to fetus [9,10]. However, there was no significant correlation between antibody titres at birth and either HIV-1 disease progression during 2 years of follow-up or mother-to-child HIV-1 transmission [9,10]. Active production of HIV-specific ADCC antibodies was observed in the majority of HIV-infected infants only after 12 months of age [10] and effector cells from HIV-1 infected children appear unable to generate NK cell-mediated cytotoxicity [11]. Thus, an immature immune system may account for the absence of ADCC-mediated NK protection against HIV-1 infection in neonates and young infants, despite adequate levels of passively transferred ADCC antibodies. This may contribute to rapid HIV-1 progression in children infected with HIV-1 early in life [10,11].

Protein Tyrosyl Phosphatases in T Cell Activation: Implication for Human Immunodeficiency Virus Transcriptional Activity

The protein tyrosine phosphatases (PTPs) superfamily is a large group of enzymes showing a wide diversity of structure and biological functions. Their implication in the regulation of signal transduction processes is critical for homeostasis and efficient cellular activation. Disturbance of the delicate balance between protein tyrosine kinase and protein tyrosine phosphatase activities is at the heart of a large number of diseases. Control of cellular activation is especially important for human immunodeficiency virus type 1 (HIV-1) since this retrovirus requires activated T cells in order to replicate efficiently. Identification of PTPs implicated in signaling pathways leading to upregulation of HIV-1 gene transcription therefore contributes to the general understanding of cellular factors needed for strong HIV-1 replication and progression to AIDS. The use of bisperoxovanadium compounds as potent, specific, and highly purified PTP inhibitors releases HIV-1 from PTP control and strongly increases HIV-1 gene expression. These inhibitors can thus be used to study signal transduction mechanisms regulated by PTP activity that are important for HIV-1 replication and provide new and interesting therapeutic avenues for the efficient control of this debilitating retroviral infection.

Initial plasma HIV-1 RNA levels and progression to AIDS in women and men.

It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men. From 1988 through 1998, the viral load and the CD4+ lymphocyte count were measured approximately every six months in 156 male and 46 female injection-drug users who were followed prospectively after HIV-1 seroconversion. The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter in the men but only 15,103 copies per milliliter in the women (P<0.001). The median initial CD4+ count did not differ significantly according to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1 infection progressed to AIDS in 29 men and 15 women, and the risk of progression did not differ significantly according to sex. For each increase of 1 log in the viral load (on a base 10 scale), the hazard ratio for progression to AIDS was 1.55 (95 percent confidence interval, 0.97 to 2.47) among the men and 1.43 (95 percent confidence interval, 0.76 to 2.69) among the women. The median initial viral load was 77,822 HIV-1 RNA copies per milliliter in the men in whom AIDS developed and 40,634 copies per milliliter in the men in whom it did not; the corresponding values in the women were 17,149 and 12,043 copies per milliliter. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74 percent of the men but only 37 percent of the women in our study would have been eligible for therapy at the first visit after seroconversion (P<0.001). Although the initial level of HIV-1 RNA was lower in women than in men, the rates of progression to AIDS were similar. Treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex.

Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs.

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.

Ethanol enhances TNF-α–inducible NFκB activation and HIV-1-LTR transcription in CD4+ Jurkat T lymphocytes

During the latent phase of human immunodeficiency virus type 1 (HIV-1) infection, CD4+ T cells carrying replication-competent proviral HIV-1 DNA play an important role in persistence of the virus. Several cofactors can induce and or amplify HIV-1 replication and negatively affect disease progression and pathogenesis. Ethanol consumption is an important risk factor for HIV-1 infection, and it has been implicated in increased HIV-1 replication and progression of infection. Because tumor necrosis factor-α (TNF-α) is an important modulator of HIV-1 replication, in the present study we examined the possible effects of ethanol on TNF-α–inducible signaling associated with HIV-1 replication in human CD4+ T cells (Jurkat E6-1). We demonstrate that clinically relevant ethanol concentrations significantly potentiate TNF-α–inducible NFκB. Although ethanol effectively collaborated with TNF-α, by itself it did not have a direct effect on NFκB activation. The ethanol-dependent potentiation of TNF-α–inducible NFκB nuclear translocation was observed to involve the enhanced degradation of IκBα. Additionally, the ethanol-mediated potentiation of TNF-α–inducible NFκB activation was abrogated by the known antioxidant pyrrolidinedithiocarbamate, suggesting an important mechanistic role for reactive oxygen species in this process. In correspondence with its effect on NFκB, ethanol was also observed to significantly enhance HIV-1 long terminal repeat–dependent transcription induced by TNF-α. Overall, the data provide a molecular basis for the possible role of ethanol as a cofactor that can adversely affect HIV-1 infection and pathogenesis. (J Lab Clin Med 2000;136:333-43)

This month in J Lab Clin Med: Issue highlights for November 2000

This month in J Lab Clin Med: Issue highlights for November 2000

Maternal clinical factors influencing HIV-1 transmission.

The complex puzzle of maternal factors involved in mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission is being put together. The risk of perinatal infection increases with mother's disease progression, but it remains stable in women seroconverting to HIV-1 during pregnancy and in consecutive pregnancies. Thus, transmission correlates with the HIV-1 progression rather than the duration of infection in the mother. Nutritional alterations such as vitamin A deficiency may also have a significant impact, whereas geographic origin and mode of maternal infection are of no influence. Placenta membrane inflammation and concurrent sexually transmitted diseases are other significant covariates. The rate of transmission appears directly correlated with maternal age and inversely with length of gestation. A protective effect of caesarean section has been reported in some observational studies but, being controversial, these results need to be corroborated by randomized trials.

Aeroallergen-specific IgE changes in individuals with rapid human immunodeficiency virus disease progression.

Progression of human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS) is associated with elevated total IgE; however, previous cross-sectional studies have differed in their assessment of concurrent changes in allergic disease prevalence. Assessment of changes in aeroallergen-specific IgE during progression from early to late HIV disease. Total IgE, aeroallergen-specific IgE (rye grass, ragweed, Alternaria, dust mite, and cat), IFN-gamma, IL-4, and soluble CD23 (sCD23) were measured in a longitudinal study of 20 subject who had progressed from early-HIV infection (mean CD4 lymphocyte count of 650/mm3) to AIDS (mean CD4 lymphocyte count of 40/mm3) over an average of 4 years. Prevalence of positive aeroallergen specific-IgE assays in early HIV disease (T1 subjects with 13 positives) decreased with progression to late disease (five subjects with nine positive, P = .057), while total IgE increased from a median of 69 to 116 IU/mL. IFN-gamma and IL-4 were unchanged, while sCD23 decreased from a median of 72 to 9 U/mL (P = .0005) with disease progression in the full cohort. In contrast to other subjects, the subgroup of individuals with total IgE > 150 IU/mL in both early and late HIV disease demonstrated an increased frequency of aeroallergen-specific IgE. The elevation of total IgE associated with rapid HIV-1 disease progression was unexplained by concurrent changes in aeroallergen-specific IgE, IL-4, IFN-gamma, or sCD23. Overall, aeroallergen-specific IgE expression was less prevalent with HIV-1 progression, except in those individuals with elevated total IgE both before and after progression to AIDS.

CD8 + cells in HIV infection produce macrophage inflammatory protein-1α and RANTES: a comparative study in long term survivors and progressor patients

Evidence suggests that CD8 + lymphocytes are involved in the control of Human Immunodeficiency virus type 1 (HIV-1) infection by the release of HIV-suppressive factors. The human chemokines RANTES and the macrophage inflammatory protein 1α (MIP-1α) have been identified to be potent inhibitors of HIV in vitro. The aim of this study was to determine whether high levels of these chemokines are associated with a delayed progression of HIV disease. We have therefore analysed the in vitro production of RANTES and MIP-1α from purified stimulated CD8 + cells from HIV + long term survivors (LTS) and, as a comparison, from HIV + patients with progressive disease. RANTES production was similar in LTS and progressors (14.06 ± 3, 13.36 ± 4.1 ng/ml, not statistically significant); the same cells from healthy controls show a RANTES production of 20 ± 3.5 ng/ml ( P = 0.034 versus LTS and P = 0.038 versus progressors). MIP-1α production was slightly reduced in LTS (96.8 ± 12 ng/ml) and progressors (91.6 ± 17, not statistically significant between the two groups) when compared to healthy controls (109 ± 7 ng/ml, P = 0.03). Our study suggests that resistance to HIV-1 progression in LTS may not be associated with high levels of RANTES and MIP-1α production.

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.