Virus Disease Progression Research Articles

Incidences and progression of tomato chlorosis virus disease and tomato yellow leaf curl virus disease in tomato under different greenhouse covers in southeast Spain

AbstractEpidemics of whitefly‐transmitted Tomato chlorosis virus, Tomato yellow leaf curl Sardinia virus and Tomato yellow leaf curl virus have been present in the south east of Spain since the 1990s. A survey was performed in 40 greenhouses and nethouses during 2003 to establish the relationship between the disease incidence and the quality of greenhouse or nethouse coverings, providing a physical protection of crops against whiteflies. For tomato chlorosis virus disease (ToCD), the incidence correlated with the type of greenhouse cover and was most reduced under higher quality covers. Control of tomato yellow leaf curl disease (TYLCD) was achieved only for crops grown in the highest quality greenhouses. TYLCD incidence in tolerant tomatoes remained below 100% within the 5 months of sampling, despite the disease progress rate at the initial stage of the cultivation being higher than that of ToCD, which did reach 100% incidence in many greenhouses. Linear regression analysis showed that the development of ToCD and TYLCD in most of the greenhouses was best described by the monomolecular model and the Gompertz model, respectively. Tomato infectious chlorosis virus was not detected in parallel surveys carried out during this study, although it has been described previously in the area studied.

Ovine progressive pneumonia provirus levels associate with breed and Ovar-DRB1

Previous studies initiated defining the role of host genetics in influencing the outcome of exposure to ovine progressive pneumonia virus. However, specific genes influencing host control of virus replication and disease progression have not been identified. This study, using 383 ewes of the Columbia, Polypay, and Rambouillet breeds, tested the hypothesis that host control of OPPV as measured by provirus levels in the peripheral blood associates with certain breeds and MHC class II Ovis aries (Ovar)-DRB1 expressed alleles. Rambouillet ewes were less likely to have measurable provirus levels as compared to Columbia ewes at ages 5 and 6 (P value < 0.02), and they exhibited lower provirus levels when compared to both Columbia and Polypay ewes of the same ages (P value < 0.05). The presence of DRB1*0403- or DRB1*07012-expressed alleles were significantly associated (P value = 0.019 and 0.0002, respectively) with lower OPP provirus levels but only were only found in 11% of the ewe flock. Analysis of each segregating amino acid in the beta1 domain of DR beta-chain revealed that amino acids Y31, T32, N37, T51, Q60, or N74 significantly associated (P value range = 0.0003-0.018) with lower OPP provirus levels, whereas amino acids H32, A38, or I67 associated (P value range = 0.013-0.043) with higher OPP provirus levels. These results suggest that Ovar-DRB1 contributes as one host genetic factor that controls OPP provirus levels, but does not fully account for the breed-specific OPP proviral differences.

Gender Differences in HIV Progression to AIDS and Death in Industrialized Countries: Slower Disease Progression Following HIV Seroconversion in Women

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposi's sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women.

Absolute CD4+ T-Lymphocyte Count as a Surrogate Marker of Pediatric Human Immunodeficiency Virus Disease Progression

Traditionally in pediatric HIV, the CD4+ T-lymphocyte percent is used to monitor disease progression because of the variability in absolute CD4+ T-lymphocyte numbers. Because of the high cost of equipment, sophisticated and delicate technology, most laboratories in resource-limited settings use simple protocols that enumerate only the absolute CD4+ T-lymphocyte counts. We assessed the use of absolute CD4+ T-lymphocyte count as a surrogate marker of pediatric HIV disease progression. We analyzed the CD4+ T-lymphocytes and HIV viral load over a 10-year period (1996-2006) of 97 HIV-infected children enrolled in the Yale Prospective Longitudinal Pediatric HIV Cohort using generalized linear mixed models. Both CD4+ T-lymphocytes and HIV viral load were assessed at baseline and every 2-3 months. The modeling approach used in this study allows the intercept and the rate at which outcome variables change over time to vary across participants. We determined that absolute CD4+ T-lymphocytes count was just as reliable at monitoring pediatric HIV as CD4+ T-lymphocyte percentage. Antiretroviral treatment, regardless of the regimen used, was associated with higher CD+ T-lymphocytes count (P < 0.01). Race was significantly associated with CD4+ T-lymphocytes counts (with lower values for blacks compared with nonblacks; P < 0.01). The presence of other infections was associated with lower CD4+ T-lymphocyte count (P = 0.01) and higher viral load (P < 0.01), respectively. In situations where determination of CD4+ T-lymphocyte percentages is not readily available, the absolute count may provide an affordable and accessible laboratory surrogate marker of HIV disease progression in children.

Mycobacterium avium infection in HIV-1-infected subjects increases monokine secretion and is associated with enhanced viral load and diminished immune response to viral antigens.

The complex interaction between HIV-1 infection and Mycobacterium avium was studied. Viral burden was assessed, as well as immune response to HIV-1 in the context of Myco. avium infections. We also examined serum cytokine levels and cytokine release by blood mononuclear cells in HIV-1-infected subjects, infected or not with Myco. avium. Undetectable serum levels of IL-1, tumour necrosis factor-alpha (TNF-alpha) and IL-6 were found in normal controls and in groups I, II and III of HIV-1-infected subjects. Moderate levels of TNF-alpha, IL-1 and IL-6 were found in the sera of group IV patients. When group IV was subdivided into subjects with and without Myco. avium infections, subjects with Myco, avium infections were shown to have higher serum levels of TNF-alpha, IL-1 beta and IL-6 than those with other infections. Blood mononuclear cells from controls and HIV subjects were stimulated with bacterial lipopolysaccharide, and cytokine levels assessed. Cells from group II patients were shown to secrete normal levels of TNF-alpha and IL-6, and lower levels of IL-1 beta; group III subjects released higher levels of IL-6. Patients in group IV had blood cells that released elevated levels of IL-6 and TNF-alpha, and lower levels of IL-1 beta. Group IV subjects with Myco. avium infections had blood cells that released higher levels of TNF-alpha, IL-6 and IL-1 than group IV subjects with other infections. Assessment of viral burden in cells of HIV-1-infected subjects revealed that Myco. avium-infected subjects had a higher level of virus burden and a lower level of lymphoproliferative response to an inactivated gp120-depleted HIV-1 antigen than AIDS subjects with other infections. These data suggest that Myco. avium infections in HIV-1-infected subjects hasten the progression of viral disease, enhance cytokine release and contribute to the anergy to viral antigens.

The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response

Arthropod-borne (arbo-) viruses have emerged as a major human health concern. Viruses transmitted by mosquitoes are the cause of the most serious and widespread arbovirus diseases worldwide and are ubiquitous in both feral and urban settings. Arboviruses, including dengue and West Nile virus, are injected into vertebrates within mosquito saliva during mosquito feeding. Mosquito saliva contains anti-haemostatic, anti-inflammatory and immunomodulatory molecules that facilitate the acquisition of a blood meal. Collectively, studies investigating the effects of mosquito saliva on the vertebrate immune response suggest that at high concentrations salivary proteins are immmunosuppressive, whereas lower concentrations modulate the immune response; specifically, T(H)1 and antiviral cytokines are downregulated, while T(H)2 cytokines are unaffected or amplified. As a consequence, mosquito saliva can impair the antiviral immune response, thus affecting viral infectiousness and host survival. Mounting evidence suggests that this is a mechanism whereby arbovirus pathogenicity is enhanced. In a range of disease models, including various hosts, mosquito species and arthropod-borne viruses, mosquito saliva and/or feeding is associated with a potentiation of virus infection. Compared with arbovirus infection initiated in the absence of the mosquito or its saliva, infection via mosquito saliva leads to an increase in virus transmission, host susceptibility, viraemia, disease progression and mortality.

CD163/CD16 Coexpression by Circulating Monocytes/Macrophages in HIV: Potential Biomarkers for HIV Infection and AIDS Progression

Monocytes and macrophages play a prominent role in the establishment of HIV-1 infection, virus dissemination, and development of viral reservoirs. Like T cells, macrophages display immune polarization that can promote or impair adaptive immunity. We hypothesize that dysregulation of monocyte/macrophage activation and differentiation may promote immune dysfunction and contribute to AIDS pathogenesis. Using flow cytometry, we analyzed the frequency of monocyte subsets in human immunodeficiency virus type 1 (HIV-1) infection relative to seronegative controls, focusing on the CD163(+)/CD16(+) monocyte as a likely precursor of the "alternatively activated" macrophage. Individuals with detectable HIV-1 infection showed an increase in the frequency of CD163(+)/CD16(+) monocytes (CD14(+)) when compared to seronegative or HIV-1-infected persons with undetectable viral loads. A positive correlation between increased CD163(+)/CD16(+) monocyte frequency and viral load was revealed that was not seen between viral load and the number of CD4(+) T cells or frequency of CD16(+) monocytes (without CD163 subtyping). We also found a strong inverse correlations between CD16(+) monocytes (r = -0.71, r(2) = 0.5041, p = 0.0097) or CD163(+)/CD16(+) monocytes (r = -0.86, r(2) = 0.7396, p = 0.0003) and number of CD4(+) T cells below 450 cells/microl. An inverse relationship between CD163(+)/CD16(+) and CD163(+)/CD16() monocytes suggests the expanded CD163(+)/CD16(+) population is derived exclusively from within the "alternatively activated" (MPhi-2) subset. These data suggest a potential role for CD163(+)/CD16(+) monocytes in virus production and disease progression. CD163(+)/CD16(+) monocytes may be a useful biomarker for HIV-1 infection and AIDS progression and a possible target for therapeutic intervention.

Associations of Insulin‐Like Growth Factor (IGF)–I and IGF‐Binding Protein–3 with HIV Disease Progression in Women

The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)-3 has an opposing effect, inhibiting hematopoietic stem cell development. We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]). Low IGF-I levels (Ptrend= .02) and high IGFBP-3 levels (Ptrend= .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30-5.42]; Ptrend= .02) in multivariable models. These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.

Dynamics of T-Cell Responses and Memory T Cells during Primary Simian Immunodeficiency Virus Infection in Cynomolgus Macaques

Cellular immune responses make an important contribution to both the control of human immunodeficiency virus (HIV) replication and disease progression. We used a pathogenic model of SIVmac251 infection of cynomolgus macaques to longitudinally evaluate cellular immune responses in association with various rates of disease progression. We found an inverse relationship between plasma viral load and the simian immunodeficiency virus (SIV)-specific T cells responses in peripheral blood and lymph nodes. SIV-specific T-cell responses in peripheral blood were transient during primary infection, with the highest responses detected around 3 months after infection. There was also a transient increase of central memory CD8(+) T cells in peripheral blood during primary infection, and effector memory T-cell counts in peripheral lymph nodes were increased. This study emphasizes the importance of the early virus-specific immune responses in the outcome of HIV/SIV disease and provides details about the changes of virus-specific immune responses over time.

A Diet High in Saturated Fat and Cholesterol Accelerates Simian Immunodeficiency Virus Disease Progression

Several lines of evidence suggest that dietary fat and cholesterol may play a role in the pathogenesis of human immunodeficiency virus (HIV) infection and disease progression. We examined the effect that an atherogenic diet (AD) high in saturated fatty acids and cholesterol has on disease progression and systemic inflammation in the simian immunodeficiency virus (SIV)-infected macaque model of acquired immunodeficiency syndrome. Macaques fed an AD had significantly more rapid disease progression, resulting in an increased risk of SIV-related death compared with that in control macaques (hazard ratio, 5.4 [95% confidence interval, 1.7-17.0]; P<.001). Peak viral load was higher in the AD group compared with control values, but further statistically significant differences were not detected at viral set point. The baseline plasma interleukin-18 level after 6 months of the AD was predictive of disease progression. Our findings may have important implications for HIV-infected individuals, because they suggest that dietary changes and manipulation of lipid metabolism could offer potential benefits by slowing disease progression.

Pregnancy and HIV Disease Progression during the Era of Highly Active Antiretroviral Therapy

Before the availability of highly active antiretroviral therapy (HAART), there was no clear effect of pregnancy on human immunodeficiency virus (HIV) disease progression. This has not been assessed during the HAART era. We conducted an observational cohort study among HIV-infected women with >or=1 outpatient clinic visit between January 1997 and December 2004. HIV disease progression was defined as the occurrence of an AIDS-defining event or death. Of 759 women who met the inclusion criteria, 139 (18%) had had >1 pregnancy, and 540 (71%) had received HAART. There was no difference in HAART duration by pregnancy status. Eleven pregnant (8%) and 149 nonpregnant (24%) women progressed to AIDS or death. After controlling for age, baseline CD4(+) lymphocyte count, baseline HIV-1 RNA level, and durable virologic suppression in a Cox proportional hazards model that included propensity score for pregnancy, pregnancy was associated with a decreased risk of disease progression (hazard ratio [HR], 0.40 [95% confidence interval {CI}, 0.20-0.79]; P=.009]). In a matched-pair analysis of 81 pregnant women matched to 81 nonpregnant women according to age, baseline CD4(+) lymphocyte count, receipt of HAART, and date of cohort entry, pregnant women had a lower risk of disease progression both before (HR, 0.10 [95% CI, 0.01-0.89]; P=.04) and after (HR, 0.44 [95% CI, 0.19-1.00]; P=.05) the pregnancy event. Pregnancy was associated with a lower risk of HIV disease progression in this HAART-era study. This finding could be the result of the healthier immune status of women who become pregnant or could possibly be related to a beneficial interaction between pregnancy and HAART.

The treatment of chronic hepatitis C in HIV‐infected patients: a meta‐analysis

Hepatitis C virus (HCV) disease progression appears to be accelerated in patients coinfected with HIV. The impact of HCV on coinfected patients is being realized as patients are now living longer. The objective of our study was to further elucidate incremental improvement and safety concerns with combinations of pegylated interferon (peginterferon), interferon and ribavirin based on data obtained from prospective randomized controlled trials. A search of MEDLINE and the Cochrane database for material published between 1966 and 29 August 2005 and a hand search of abstracts from national meetings held between 2001 and August 2005 were performed. Trials comparing the use of peginterferon plus ribavirin vs peginterferon or interferon plus ribavirin were assessed. In six randomized controlled trials, 1756 patients were randomized. Sustained virological response was greater for patients treated with peginterferon plus ribavirin compared with patients treated with interferon plus ribavirin [odds ratio (OR) 3.00; 95% confidence interval (CI) 2.27-3.96]. This increased sustained virological response with peginterferon and ribavirin was found for patients with HCV genotype 1 or 4 (OR 4.40; 95% CI 2.75-7.03) and genotype 2 or 3 (OR 2.56; 95% CI 1.71-3.85). Sustained virological responses were also higher with peginterferon and ribavirin as compared with peginterferon monotherapy (OR 2.60; 95% CI 1.84-3.67). Severe adverse effects (OR 1.09; 95% CI 0.74-1.4) and withdrawal rates (OR 0.97; 95% CI 0.75-1.25) were similar between patients treated with peginterferon plus ribavirin and patients treated with interferon plus ribavirin. Patients with chronic HCV/HIV coinfection have a greater likelihood of achieving a sustained virological response with peginterferon plus ribavirin. The likelihoods of serious adverse effects and study withdrawal were similar.

Characteristics and survival of HIV‐infected patients not screened for hepatitis C virus infection in a hospital‐based cohort

The rate of human immunodeficiency virus (HIV) disease progression or death of individuals coinfected with hepatitis C virus (HCV) is conflicting. The complete-case analysis systematically used, excludes patients unscreened for HCV. Our objective was to assess if rate of survival differed between HIV-infected patients screened and unscreened for HCV in a hospital-based prospective cohort study. Patients were enrolled in the Lyon section of the French Hospital Database on HIV between 1 July 1992 and 31 May 2005. A multivariate Cox regression model was used to analyse the association of HCV screening with survival. Of 3244 patients, 299 (9.2%) were not screened for HCV. The populations screened and unscreened differed by the proportion of acquired immune deficiency syndrome at baseline, presumed route of infection, CD4 cell count category at baseline, mean duration of follow-up, mean number of visits per year, type of antiretroviral therapy and survival. The rate of progression to death was higher for non-HCV-screened vs HCV-screened patients: the incidence rate among HCV-screened patients was 22.9/1000 patient-years; the incidence rate among HCV-unscreened patients was 52.4/1000 patient-years. The adjusted hazards ratio of death was 2.48 [95% confidence interval (1.83-3.35); P < 0.001] for patients with unknown HCV status compared with others. In conclusion, unscreened or unknown HCV status was associated with an increased risk of death in our hospital cohort. Important prognostic factors are related to, or confounded by the practice of HCV screening.

Effects of Human Leukocyte Antigen Class I Genetic Parameters on Clinical Outcomes and Survival after Initiation of Highly Active Antiretroviral Therapy

Human leukocyte antigen (HLA) class I variation influences the progression of untreated human immunodeficiency virus (HIV) disease; however, it is not known whether HLA class I variation may influence clinical outcomes after initiation of highly active antiretroviral therapy (HAART). Associations between HLA class I genotypes and pretherapy clinical parameters were investigated in a cohort of 765 antiretroviral-naive adults initiating HAART. Cox proportional hazards regression was used to investigate the effects of HLA class I genotypes on time to suppression of the viral load to <500 HIV RNA copies/mL, time to an increase in the CD4 cell count to >100 cells/mm(3) above the baseline count, and time to nonaccidental death over a >5-year period after initiation of HAART. Homozygosity at any HLA class I locus and possession of common HLA alleles were associated with a higher pretherapy viral load (P<.05). In multivariate analyses controlling for sociodemographic and clinical parameters at baseline, HLA class I homozygosity was significantly associated with a poorer CD4 cell response (P=.008), whereas possession of uncommon HLA alleles was associated with slower virologic suppression after initiation of HAART (P=.02). We observed no significant association between HLA parameters and time to nonaccidental death after initiation of HAART (P>.05, univariate analysis). HLA class I zygosity-dependent and frequency-dependent effects may influence short-term HAART outcomes, and, thus, they deserve further investigation. No effects of these HLA parameters on survival after initiation of HAART were observed.

Association of killer immunoglobulin‐like receptors and their HLA Class I ligands with progression of chronic hepatitis C virus infection

This part of the workshop addressed the results of a study on killer immonoglobulin-like receptors and hepatitis C virus disease progression.

Human herpesvirus 6A accelerates AIDS progression in macaques.

Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4(+) T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development in dually infected animals was heralded by an early depletion of both CD4(+) and CD8(+) T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression.

Interaction of HTLV-1 Tax protein with calreticulin: Implications for Tax nuclear export and secretion

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 transcriptional transactivator protein Tax plays an integral role in virus replication and disease progression. Traditionally, Tax is described as a nuclear protein where it performs its primary role as a transcriptional transactivator. However, recent studies have clearly shown that Tax can also be localized to the cytoplasm where it has been shown to interact with a number of host transcription factors most notably NF-κB, constitutive expression of which is directly related to the T cell transforming properties of Tax in ATL patients. The presence of a functional nuclear export signal (NES) within Tax and the secretion of full-length Tax have also been demonstrated previously. Additionally, release of Tax from HTLV-1-infected cells and the presence of cell-free Tax was demonstrated in the CSF of HAM/TSP patients suggesting that the progression to HAM/TSP might be mediated by the ability of Tax to function as an extracellular cytokine. Therefore, in both ATL and HAM/TSP Tax nuclear export and nucleocytoplasmic shuttling may play a critical role, the mechanism of which remains unknown. In this study, we have demonstrated that the calcium binding protein calreticulin interacts with Tax by co-immunoprecipitation. This interaction was found to localize to a region at or near the nuclear membrane. In addition, differential expression of calreticulin was demonstrated in various cell types that correlated with their ability to retain cytoplasmic Tax, particularly in astrocytes. Finally, a comparison of a number of HTLV-1-infected T cell lines to non-infected T cells revealed higher expression of calreticulin in infected cells implicating a direct role for this protein in HTLV-1 infection.

Effect of Tuberculosis on the Survival of Women Infected with Human Immunodeficiency Virus

Evidence regarding the effect of tuberculosis (TB) disease on progression of human immunodeficiency virus (HIV) disease is inconclusive. The authors estimated the effect of time-varying incident TB on time to acquired immunodeficiency syndrome (AIDS)-related mortality using a joint marginal structural Cox model. Between 1995 and 2002, 1,412 HIV type 1 (HIV-1)-infected women enrolled in the Women's Interagency HIV Study were followed for a median of 6 years. Twenty-nine women incurred incident TB, and 222 died of AIDS-related causes. Accounting for age, CD4 cell count, HIV-1 RNA level, serum albumin level, and non-TB AIDS at study entry, as well as for time-varying CD4 cell count, CD4 cell count nadir, HIV-1 RNA level, peak HIV-1 RNA level, serum albumin level, HIV-related symptoms, non-TB AIDS, anti-Pneumocystis jiroveci prophylaxis, antiretroviral therapy, and household income, the hazard ratio for AIDS-related death comparing time after incident TB with time before incident TB was 4.0 (95% confidence interval (CI): 1.2, 14). The effect of incident TB on mortality was similar among highly active antiretroviral therapy (HAART)-exposed women (hazard ratio = 4.3, 95% CI: 0.9, 22) and non-HAART-exposed women (hazard ratio = 3.9, 95% CI: 0.9, 17; interaction p = 0.91). Although results were imprecise because few women incurred TB, irrespective of HAART exposure, incident TB increases the hazard of AIDS-related death among HIV-infected women.

Mechanisms of CD4 Downregulation by the Nef and Vpu Proteins of Primate Immunodeficiency Viruses

Human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) are the etiological agents of acquired immunodeficiency syndrome (AIDS) in humans and a related disease in non-human primates. These viruses infect T cells and macrophages that express the surface glycoprotein, CD4, because this glycoprotein acts as a co-receptor for incoming virus particles. Once infection has occurred, however, the presence of CD4 poses problems for the virus life cycle, including the possibility of superinfection, premature binding of CD4 to nascent virus particles, and inhibition of virus release. Accordingly, primate immunodeficiency viruses have evolved at least two distinct mechanisms, mediated by the Nef and Vpu viral proteins, to "downregulate" CD4 in the host cells. Nef and Vpu are mainly expressed early and late, respectively, in the viral life cycle, ensuring continuous removal of CD4. Nef links mature CD4 to components of clathrin-dependent trafficking pathways at the plasma membrane, and perhaps in intracellular compartments, leading to internalization and delivery of CD4 to lysosomes for degradation. Vpu, on the other hand, interacts with newly-synthesized CD4 in the endoplasmic reticulum, linking CD4 to the SCF ubiquitin ligase and facilitating the entry of CD4 into the endoplasmic-reticulum-associated degradation pathway. These two mechanisms lead to a dramatic reduction of CD4 expression in infected cells and are essential for efficient virus replication and disease progression.

Accelerated progression to AIDS in macaques coinfected with simian immunodeficiency virus and human herpesvirus 6A

Although HIV-1 is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6 (HHV-6), a cytopathic T-lymphotropic agent, may act as an accelerating factor in the progression of HIV disease, although conclusive in vivo evidence has yet to be attained. To evaluate the effect of HHV-6A on the course of AIDS in a relevant model system, we infected pig-tailed macaques (M. nemestrina) either with HHV-6A (strain GS) or with a pathogenic SIV strain (smE660), or with both viruses. Extensive longitudinal virologic, immunologic and clinical follow-up demonstrated that HHV-6A coinfection dramatically accelerated the progression toward full-blown AIDS. Rapid disease development in coinfected animals was associated with an early depletion of both CD4+ and CD8+ T cells. Simultaneous replication of both viruses was documented in coinfected lymph node tissue. These data establish a new animal model for the study of HHV-6 infection and provide the first conclusive in vivo evidence that HHV-6A acts as a cofactor in the progression of primate immunodeficiency virus disease.