Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: implications for antiviral therapy.

Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mostly present in individual virus-expressing cells in LNs; trapping of virions in the follicular dendritic cell (FDC) network was minimal or absent, but was the predominant form of HIV detected in LNs of subjects with chronic infection, either recent (4-20 months after primary infection) or long-term (>2-3 years after primary infection). Plasma viremia was significantly higher in patients during the first 3 months than in those recently infected; however, there were no significant differences in the number of virus-expressing cells per square millimeter of LN tissue in these two groups. Numbers of virus-expressing cells in lymphoid tissue were significantly lower in the subjects with long-term infection than in the other two groups. Therefore, during the transition from primary to chronic HIV infection, the level of HIV replication in lymphoid tissue remains elevated despite the fact that viremia is significantly downregulated. These findings have implications for therapeutic strategies in primary HIV infection and in recent seroconvertors.

Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.

In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies.

Although the development of a fully protective HIV vaccine is the ultimate goal of HIV research, to date only one HIV vaccine trial, the RV144, has successfully induced a weakly protective response. The 31% protection from infection achieved in the RV144 trial was linked to the induction of nonneutralizing antibodies, able to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), suggestive of an important role of Fc-mediated functions in protection. Similarly, Fc-mediated antiviral activity was recently shown to play a critical role in actively suppressing the viral reservoir, but the Fc effector mechanisms within tissues that provide protection from or after infection are largely unknown. Here we aimed to define the landscape of effector cells and Fc receptors present within vulnerable tissues. We found negligible Fc receptor-expressing natural killer cells in the female reproductive and gastrointestinal mucosa. Conversely, Fc receptor-expressing macrophages were highly enriched in most tissues, but neutrophils mediated superior antibody-mediated phagocytosis. Modifications in Fc domain of VRC01 antibody increased phagocytic responses in both phagocytes. These data suggest that non-ADCC-mediated mechanisms, such as phagocytosis and neutrophil activation, are more likely to play a role in preventative vaccine or reservoir-eliminating therapeutic approaches.

Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials.

Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.

Primary HIV infection. Early diagnosis and treatment are critical to outcome.

It is now apparent that early identification of primary HIV infection is important, because events occurring in early disease may predict how fast a patient progresses to AIDS. However, as Dr Schacker points out, diagnosis is not easy at this stage. This article describes clinical features and laboratory tests to help primary care physicians make a timely diagnosis and discusses current recommendations for therapy.

High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage.

The mechanisms underlying the massive gastrointestinal tract CD4 T-cell depletion in human immunodeficiency virus (HIV) infection are not well understood nor is it clear whether similar depletion is manifest at other mucosal surfaces. Studies of T-cell and virus dynamics in different anatomical sites have begun to illuminate the pathogenesis of HIV-associated disease. Here, we studied depletion and HIV infection frequencies of CD4 T cells from the gastrointestinal tract, bronchoalveolar lavage (BAL), and blood with the frequencies and functional profiles of HIV-specific T cells in these anatomically distinct sites in HIV-infected individuals. The major findings to emerge were as follows: (i) depletion of gastrointestinal CD4 T cells is associated with high frequencies of infected CD4 T cells; (ii) HIV-specific T cells are present at low frequencies in the gastrointestinal tract compared to blood; (iii) BAL CD4 T cells are not massively depleted during the chronic phase; (iv) infection frequencies of BAL CD4 T cells are similar to those in blood; (v) significantly higher frequencies and increased functionality of HIV-specific T cells were observed in BAL compared to blood. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might circumvent global depletion of mucosal CD4 T cells.

The role of HSV in the transmission and progression of HIV.

Herpes simplex virus (HSV) is a common co-infection in persons infected with human immunodeficiency virus type 1 (HIV-1). Chronic perianal ulceration from herpes simplex virus type 2 (HSV-2) was one of the first opportunisitc infections identified among patients with AIDS. Subsequent research has established that the natural history of HSV-2 is altered in co-infected persons as they experience more frequent clinical and subclinical reactivation of HSV than persons infected only with HSV-2. In addition, there are accumulating data to suggest a significant biological interaction between these two viruses that result in more efficient sexual transmission of HIV-1 and an increased rate of HIV replication during both clinical and subclinical HSV reactivation.

Primary HIV infection.

AIDS: A study is underway at the University of Washington to determine factors predominant in the progression of HIV to AIDS. Information on this subject has been limited because few studies targeted people shortly after seroconversion. Seroconversion to HIV usually occurs 10 to 14 days after exposure, and symptoms are frequently mistaken for mononucleosis. CD4 changes, HIV viral load levels, and potential drug therapy (with its associated side effects) are discussed in relation to primary HIV infections.^ieng

HSV-2 and HIV: consequences of an endemic opportunistic infection.

AIDS: People with HIV are also frequently co-infected with herpes simplex viruses (HSV), although the interactions between the two are not fully understood. Evidence suggests that HSV is a risk factor for the transmission of HIV, is a common opportunistic pathogen in HIV-infected persons, and that HSV reactivation appears to regulate HIV replication. The clinical significance of these interactions is not well defined. Current information about the HSV-HIV interaction is reviewed, and future research projects are suggested. Advanced HIV infection has been associated with genital herpes, and unusually severe outbreaks of genital herpes and persistent herpetic ulcerations are an AIDS-defining diagnosis. Chronic anti-HSV therapy may be beneficial in some persons with HIV. Studies are being designed to address some of the outstanding issues in understanding the links between the two infections, and potential volunteers in the trials are invited to participate. Contact the University of Washington Virology Research Clinic for further information.^ieng

Topical treatment of infection with acyclovir-resistant mucocutaneous herpes simplex virus with the ribonucleotide reductase inhibitor 348U87 in combination with acyclovir.

The thiocarbonohydrazone 348U87 inactivates herpes simplex virus ribonucleotide reductase and potentiates the activity of acyclovir against wild-type and acyclovir-resistant strains of herpes simplex virus. We treated 10 human immunodeficiency virus-infected patients with acyclovir-resistant anogenital herpes simplex virus infection with a topical preparation of 348U87 (3%) in combination with acyclovir (5%) in an open-labelled study. Transient improvement with combination therapy occurred frequently; however, target lesions reepithelialized completely in only 1 of 10 patients. Termination of study drug therapy was most often due to cessation of therapeutic effect before complete resolution of lesions. As currently formulated, topical 348U87 offers little therapeutic benefit for this indication.

Human herpesvirus 6 DNA in blood cells of human immunodeficiency virus-infected men: correlation of high levels with high CD4 cell counts.

The relationship between human herpesvirus 6 (HHV-6) and the progression of human immunodeficiency virus type 1 (HIV-1) infection to AIDS was evaluated using the polymerase chain reaction to quantitate HHV-6 genome equivalents in peripheral blood mononuclear cells (PBMC) and saliva of 32 HIV-1-seropositive men. Unlike other herpesviruses, HHV-6 was found with higher frequency and in higher copy numbers of HIV-infected men with high rather than low CD4 cell counts. Among subjects with > 400 CD4 cells/mL, 100% had detectable HHV-6 genomes in PBMC compared with 57.9% of subjects with < 400 CD4 cells/mL (P < .05). There was no significant correlation between HHV-6 antibody titer or number of amplifiable copies of HHV-6 DNA in saliva and stage of HIV disease or CD4 cell number.

Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men.

Herpes simplex virus (HSV) infection is common in persons coinfected with human immunodeficiency virus (HIV). In a prospective study, daily viral cultures of the mouth, genitals, and rectum were collected from 68 HIV-positive and 13 HIV-negative men who have sex with men. Subjects completed a median of 57 days of follow-up. Anogenital HSV-2 cultures were positive on 405 (9.7%) of 4167 days for HIV-positive men and on 24 (3.1%) of 766 days for HIV-negative men. Most reactivations were perirectal and subclinical. Risk factors for increased HSV-2 shedding among HIV-positive men were low CD4 cell count (odds ratio, 2.5; 95% confidence interval, 1.2-5.4) and antibodies to both HSV-1 and HSV-2 versus HSV-2 only (odds ratio, 1.9; 95% confidence interval, 1.0-3.7). Three isolates obtained from 3 separate subjects were resistant to acyclovir. Thus, subclinical HSV-2 reactivation is an important opportunistic infection in persons with HIV infection. Further studies are necessaryto determine the impact of subclinical HSV-2 reactivation on the natural history of HIV infection.

The relationship between tumor necrosis factor and human immunodeficiency virus gene expression in lymphoid tissue.

In tissue culture models of chronic human immunodeficiency virus type 1 (HIV-1) infection, cytokines such as tumor necrosis factor alpha (TNF-alpha) activate viral gene expression. We sought evidence that TNF-alpha might similarly regulate viral gene expression in vivo in the major lymphoid tissue (LT) reservoir. We used in situ hybridization, quantitative image analysis, and double-label techniques to compare cytokine and HIV-1 RNA levels in sections of tonsil and lymph node tissues obtained from individuals in early and later stages of HIV-1 infection. The levels of TNF-alpha gene expression in LT from HIV-1-infected an uninfected individuals were indistinguishable, and we found no correlation between TNF-alpha gene expression in LT and the level of HIV-1 gene expression in LT. There is thus little evidence that in vivo TNF-alpha significantly influences HIV production in LT.

Biological and virologic characteristics of primary HIV infection.

BACKGROUND: The clinical events surrounding acute HIV-1 infection have been well described, but little is known about whether the virologic course of acute HIV-1 infection influences the subsequent progression of disease. OBJECTIVE: To define the virologic natural history of acute and very early HIV infection. DESIGN: Prospective, longitudinal cohort study. SETTING: University of Washington Research Clinic PARTICIPANTS: 74 adults enrolled soon after acquisition of HIV (mean, 69 days). MEASUREMENTS: Plasma HIV-1 RNA levels; quantitative cell cultures; CD4 cell counts; and detailed clinical assessments done at study entry, biweekly for 1 month, monthly for 2 months, and quarterly thereafter. RESULTS: In the first 30 days after acquisition of HIV, HIV-1 RNA levels varied greatly among participants (range, 27,200 to 1.6 x 10(6) copies per mL of plasma). Levels of HIV-1 RNA decreased by a mean of 6.5% per week for the first 120 days and then increased by a mean of 0.15% per week. CD4 cell counts decreased by a mean of 5.2 cells/mm3 per week for the first 160 days and by a mean of 1.9 cells/mm3 per week thereafter (P < 0.01). Disease progressed faster in participants who sought medical care for their acute seroconversion syndrome (P = 0.01) and those who had high plasma HIV-1 RNA levels 120 to 365 days after acquisition (P < 0.01). Peak levels in the first 120 days were not predictive of disease progression. CONCLUSIONS: The variability in viral RNA levels associated with acute HIV-1 infection is greater than previously appreciated. Within 120 days of acquisition, plasma HIV RNA levels rapidly decrease to an inflection point, after which they gradually increase. Virus-host interactions soon after acquisition seem to have a major influence on the long-term outcome of HIV-1 disease.

Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men.

CONTEXT: Genital ulcer disease has been epidemiologically linked as a risk factor in the transmission of the human immunodeficiency virus 1 (HIV-1). While herpes simplex virus 2 (HSV-2) is the most common cause of genital ulcers, no study has systematically evaluated the frequency or titer of HIV-1 virus in HSV-2 lesions. OBJECTIVE: To compare lesional HIV-1 RNA levels during and after genital HSV-2 reactivation and to evaluate the frequency, titer, and duration of HIV-1 RNA shedding in lesions due to HSV-2. DESIGN: Convenience sample. SETTING: Sexually transmitted disease research clinic at the University of Washington, Seattle. PATIENTS: Twelve HIV-infected men with a history of symptomatic HSV-2 infection who underwent daily sampling of genital lesions for HIV-1 RNA by polymerase chain reaction assay and HSV-2 by culture. MAIN OUTCOME MEASURE: Detection of lesional HIV RNA and HSV-2. RESULTS: HIV-1 RNA was detected from lesional swabs in 25 of 26 consecutively studied HSV-2 episodes and on 67% of days in which genital lesions were noted. The HIV-1 RNA titers in lesional swabs exceeded 10000 copies/mL of swab sample in 75% of samples (range, 2.2-3.2 x 10(5) copies/mL of swab sample). HIV-1 RNA in genital lesion swabs was seen in persons with high and low titers of plasma HIV-1 RNA and was not associated with plasma HIV-1 RNA levels. CONCLUSIONS: HIV-1 virions can consistently be detected in genital ulcers caused by HSV-2, which suggests that genital herpes infection likely increases the efficiency of the sexual transmission of HIV-1.

Clinical and epidemiologic features of primary HIV infection.

BACKGROUND: The acute clinical events surrounding the acquisition of human immunodeficiency virus (HIV) have not been well characterized. OBJECTIVE: To further define the clinical and epidemiologic presentation of primary HIV infection. DESIGN: Descriptive cohort study. SETTING: University research clinic. PATIENTS: 46 adults (43 men and 3 women) with primary HIV infection who enrolled in the study a median of 51 days after HIV seroconversion. MEASUREMENTS: Documentation of recent HIV seroconversion. Standardized collection of demographic characteristics and sexual contact history, results of tests for HIV RNA, HIV culture, and T-cell subsets. RESULTS: 41 of 46 patients (89%) developed an acute retroviral syndrome. Primary HIV infection was infrequently diagnosed at the initial medical encounter, even in persons enrolled in routine HIV screening programs. Median numbers of sexual partners 6 months and 1 month before acquisition of HIV were three and one, respectively; 21 patients (46%) reported having had only one partner in the month before seroconversion. Of the 12 patients who could identify the precise date of and activity leading to seroconversion, 4 reported having only oral-genital contact. CONCLUSIONS: Primary HIV infection causes a recognizable clinical syndrome that is often underdiagnosed, even in persons enrolled in a program of routine surveillance for HIV infection. Frequency of sexual contact and overall numbers of sexual partners in this group of homosexual men who acquired HIV were markedly lower than those seen a decade ago. Acquisition of HIV does occur, even in persons with relatively few sexual partners. Increased attention to oral-genital contact as a means of acquiring HIV appears to be warranted.

Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection.

BACKGROUND: Early in human immunodeficiency virus type 1 (HIV-1) infection there is a decline in viral replication that has been attributed to host immunity, but the components of this response, particularly the ability of cytotoxic T lymphocytes to control viral burden and influence the outcome of disease, are poorly understood. METHODS: We prospectively studied 33 patients with primary HIV-1 infection for HIV-specific activated cytotoxic T lymphocytes and memory cytotoxic T lymphocytes and compared these lymphocyte responses with changes in viral load and clinical status over the subsequent 18 to 24 months. RESULTS: Soon after infection, activated HIV-specific cytotoxic T lymphocytes, mediated primarily by CD8+ cells, were detected in 17 of 23 patients (74 percent). Memory cytotoxic T lymphocytes were found in 6 of 6 patients tested (100 percent) during the first three months of infection and in 17 of 21 patients (81 percent) tested during the first six months. The frequencies of memory cytotoxic T lymphocytes varied markedly over time, but overall they declined over the first 6 to 8 months and then stabilized over the next 12 to 18 months. The patients with higher frequencies of Env-specific memory cytotoxic T lymphocytes had a median level of plasma HIV-1 RNA about one third that of the patients with lower frequencies, (median number of RNA copies per milliliter, 22,000 vs. 62,000; P=0.006). Patients with low frequencies of Env-specific memory cytotoxic T lymphocytes (or none) in early infection had a more rapid decline to less than 300 CD4+ cells per cubic millimeter (P = 0.05). CONCLUSIONS: In early HIV-1 infection, the induction of memory cytotoxic T lymphocytes, particularly those specific for Env, helps control viral replication and is associated with slower declines in CD4+ cell counts. Host cytolytic effector responses appear to delay the progression of HIV-1 disease.

Potential for combined therapy with 348U87, a ribonucleotide reductase inhibitor, and acyclovir as treatment for acyclovir-resistant herpes simplex virus infection.

Inhibitors of the ribonucleotide reductase of herpes simplex viruses (HSV) potentiate the activity of acyclovir in vitro and in animal studies. In addition, the combination of the ribonucleotide reductase inhibitor 348U87 and acyclovir has synergistic therapeutic effects against infections in mice due to thymidine kinase-deficient, thymidine kinase-altered, and DNA polymerase mutants of HSV. We performed a pilot study of topical combination therapy with 348U87 (3%) and acyclovir (5%) cream for acyclovir-resistant, anogenital HSV infections in ten human immunodeficiency virus (HIV)-infected patients. Our results, with lack of complete reepitheliazation of lesions in all patients and poor virologic response, suggest that this therapy is unlikely to be useful for this indication.

Herpes simplex virus seropositivity and reactivation at delivery among pregnant women infected with human immunodeficiency virus-1.

OBJECTIVE: Our purpose was to determine whether pregnant women infected with human immunodeficiency virus-1 have an increased risk of herpes simplex virus-2 seropositivity and herpes simplex virus reactivation at delivery. STUDY DESIGN: Sixty women infected with human immunodeficiency virus and 8408 other patients who were delivered at the University of Washington between 1989 and 1995 had herpes simplex virus serologic determinations at delivery. Genital herpes simplex virus cultures were obtained for 48 (80%) of the human immunodeficiency virus-infected women and 5567 (66%) of the controls. Logistic regression was used to adjust for possible confounding factors. RESULTS: Forty-five (75%) of human immunodeficiency virus-infected women and 2709 (32%) controls were seropositive for herpes simplex virus-2 (p < 0.0001). Eight percent of human immunodeficiency virus-infected women and 2% of controls had herpes simplex virus reactivation in labor (p < 0.05). CONCLUSIONS: Infection with herpes simplex virus-2 is common among pregnant women infected with human immunodeficiency virus. Herpes simplex virus reactivation complicates labor in this group more often than in other obstetric patients. The role of herpes simplex virus in perinatal human immunodeficiency virus transmission warrants further study.

Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses.

The rate of progression to AIDS in human immunodeficiency virus type 1 (HIV-1)-infected individuals is determined by a complex series of interactions between the host and virus. Here we evaluate virologic properties and host responses in two men near-simultaneously infected with HIV-1 from the same sexual partner--one individual progressed to AIDS in less than 2 years, and the other remains asymptomatic 3 years postinfection. Distinct neutralizing antibody and cellular immune responses were evident, with the slower progressor exhibiting generally stronger and broader responses, except for cytotoxic T-lymphocyte responses early in infection. Virtually identical, homogeneous virus populations were found in both patients in the first sample obtained; however, a second unrelated HIV-1 virus population was also found in the fast progressor. Whether the second population emanated from an additional source of infection or the two were transmitted from the original source could not be determined. The virus population in the slower progressor turned over and diversified rapidly, whereas both virus populations in the rapid progressor evolved at a much slower rate. In addition, the character of mutational changes underlying these diversities appeared to be distinct, with a bias for diversifying selection developing in the slower progressor and a reciprocal bias towards purifying selection maintained in both populations in the fast progressor. Thus, the rapid evolution that is a hallmark of HIV replication may be a reflection of strong host resistance against emerging virus variants and a longer period of asymptomatic infection. Furthermore, rapid progression was not linked to a collapse of any appreciable immune response following attainment of some threshold of antigenic diversity but rather to a failure to drive this diversification and a condition of relatively unimpeded expansion of variants with optimized replicative capacity within the host.