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.

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.

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.

Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS.

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

Productive infection of T cells in lymphoid tissues during primary and early human immunodeficiency virus infection.

Current models suggest that during human immunodeficiency virus type 1 (HIV-1) transmission virions are selected that use the CCR5 chemokine receptor on macrophages and/or dendritic cells. A gradual evolution to CXCR4 chemokine receptor use causes a shift in the proportion of productively infected cells to the CD4 cell population. Productively infected cells during acute and early infection in lymphoid tissue were assessed, as well as the impact of productive infection on the T cell population in 21 persons who had biopsies performed on days 2-280 after symptoms of acute HIV-1 seroconversion. Even in the earliest stages of infection, most productively infected cells were T lymphocytes. There were sufficient infected cells in lymphoid tissue (LT) to account for virus production and virus load in plasma. Despite the relatively high frequency of productively infected cells in LT, the impact on the size of the T cell population in LT at this stage was minor.

Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir.

Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.

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.

Mucosal shedding of human herpesvirus 8 in men.

BACKGROUND: Epidemiologic studies suggest that human herpesvirus 8 (HHV-8) is sexually transmitted among men who have sex with men; however, the mode of transmission is unclear. METHODS: To evaluate the patterns of shedding of HHV-8, we obtained mucosal-secretion samples from a cohort of HHV-8-seropositive men who had sex with men and had no clinical evidence of Kaposi's sarcoma. Quantitative polymerase-chain-reaction (PCR) assays, in situ PCR assays, and in situ RNA hybridization were used to identify potential sources of infectious HHV-8. RESULTS: We detected HHV-8 in at least one mucosal sample from 30 of 50 men who were seropositive for HHV-8 (60 percent). Overall, HHV-8 was detected in 30 percent of oropharyngeal samples, as compared with 1 percent of anal and genital samples (P<0.001). In 39 percent of the HHV-8-seropositive men, HHV-8 was detected in saliva on more than 35 percent of the consecutive days on which samples were obtained. The median log titer of HHV-8 from the oral cavity was approximately 2.5 times as high as the titer at all other sites. In situ hybridization studies indicated that HHV-8 DNA and messenger RNA were present in oral epithelial cells. Among 92 men who had sex with men and who were seronegative for the human immunodeficiency virus (HIV), a history of sex with a partner who had Kaposi's sarcoma, deep kissing with an HIV-positive partner, and the use of amyl nitrite capsules ("poppers") or inhaled nitrites were independent risk factors for infection with HHV-8. CONCLUSIONS: Oral exposure to infectious saliva is a potential risk factor for the acquisition of HHV-8 among men who have sex with men. Hence, currently recommended safer sex practices may not protect against HHV-8 infection.

Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection.

T-cell responses were evaluated prospectively in 41 patients with acute human immunodeficiency virus type 1 (HIV-1) infection (30 untreated and 11 receiving zidovudine, lamivudine, and indinavir) and in 38 uninfected adults. By 6-12 months, treated patients had significantly greater median Candida and tetanus lymphoproliferative responses (stimulation index [SI], 76 and 55, respectively) than did untreated patients (SI, 7 and 6, P=.02 and.001, respectively), and the responses of treated patients surpassed those of uninfected adults (SI, 19 and 32, P= .002 and .101, respectively). Unlike the patients in the untreated group, the patients in the treated group mounted a 6-fold increased HIV-1 p24 response (SI increase, 1.0 to 5.7, P= .01) within 3 months. HIV-1-specific cytotoxicity remained detectable in most treated patients. Thus, combination therapy administered within 3-4 months of infection was associated with improved T-cell memory responses that were distinct from those of untreated patients. The amplified HIV-1-specific T-cell responses may help maintain cytotoxic activities.

Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy.

The follicular dendritic cell network (FDC) in lymphoid tissues (LTs) is the major site of human immunodeficiency virus (HIV) storage in presymptomatic and late stages of disease. However, little is known about the rate of virus accumulation during the acute and early stages. In situ hybridization and quantitative image analysis were used to determine the amount of virus bound to the FDC network during the first year of infection. The FDC pool was already >7.0 log10 copies of HIV RNA/g LT in the first year, and 2 patients biopsied within 2-4 days of symptom onset had 7.3 and 8.2 log10 copies of HIV RNA/g LT, respectively. There was no correlation between duration of infection and accumulation of HIV into the FDC network. These data suggest that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network.

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.

Early and persistent human immunodeficiency virus type 1 (HIV-1)-specific T helper dysfunction in blood and lymph nodes following acute HIV-1 infection.

Without potent antiretroviral therapy, most human immunodeficiency virus type 1 (HIV-1)-infected persons experience a progressive decline in CD4+ T cells and impairment in T helper function. It is unclear how soon after infection T cell dysfunction occurs. T helper responses were examined in blood and lymphoid tissue of 39 untreated patients with acute HIV-1 infection. Within the first 3 months, lymphoproliferative responses to mitogen, recall antigens, and HIV-1 antigens were impaired. After 6-9 months, responses to phytohemagglutinin and recall antigens improved. However, HIV-1-specific lymphoproliferation remained largely undetectable throughout 2 years of infection, and results were similar upon evaluation of lymphoid cells. Rare patients with HIV-1-specific responses had significantly lower plasma HIV-1 RNA levels than did nonresponders. These results indicate that T helper dysfunction occurs early after HIV-1 acquisition and that untreated individuals rarely recover HIV-specific helper responses; these findings lend support for early therapeutic intervention to prevent the destruction and further impairment of the T helper cells.

Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection.

Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.

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.

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.

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.

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.

Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial.

BACKGROUND: Herpes simplex virus (HSV) infection is one of the most common opportunistic infections in HIV-infected persons. However, most documentation of the effectiveness of antiviral therapy in reducing HSV reactivation is anecdotal. OBJECTIVE: To evaluate the quantitative effect of antiviral therapy on the frequency of HSV reactivation in HIV-infected persons. DESIGN: Double-blind, placebo-controlled, crossover trial. SETTING: Research clinic at a university hospital. PATIENTS: 48 persons (45 men and 3 women) who were HIV positive and HSV seropositive. INTERVENTION: Patients were randomly assigned to receive famciclovir, 500 mg orally twice daily, or placebo for 8 weeks. They then crossed over to receive the other regimen after a 1-week washout period. MEASUREMENTS: Patients obtained daily cultures of their perirectal, urethral, oral, and genital areas and kept dairy records of signs and symptoms of genital and oral-labial herpes. RESULTS: The median CD4 cell count at study entry was 384 cells/mm3. In the intention-to-treat analysis of the first study period, HSV was isolated on 122 of 1114 (11%) placebo days compared with 9 of 1071 (1%) famciclovir days (relative risk, 0.15; P < 0.001). For patients who completed the crossover, the median difference in days with symptoms between placebo and famciclovir was 13.8% of days and the median difference in days on which HSV was isolated was 5.4% of days (P < 0.001 for both). Percentage of days with HSV-2 shedding was reduced from 9.7% to 1.3%. Breakthrough reactivations that occurred while patients were receiving famciclovir were infrequent, short, and often asymptomatic, HSV-2 isolates from these reactivations were susceptible to penciclovir in vitro. CONCLUSIONS: Antiviral chemotherapy with famciclovir results in clinically and statistically significant reductions in the symptoms associated with HSV infection and the symptomatic and asymptomatic shedding of HSV among HIV-positive persons.

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.