Perinatal transmission of major, minor, and multiple maternal human immunodeficiency virus type 1 variants in utero and intrapartum.

Previous studies have provided conflicting data on the presence of selective pressures in the transmission of a homogeneous maternal viral subpopulation to the infant. Therefore, the purpose of this study was to definitively characterize the human immunodeficiency virus type 1 (HIV-1) quasispecies transmitted in utero and intrapartum. HIV-1 envelope gene diversity from peripheral blood mononuclear cells and plasma was measured during gestation and at delivery in mothers who did and did not transmit HIV perinatally by using a DNA heteroduplex mobility assay. Children were defined as infected in utero or intrapartum based on the timing of the first detection of HIV. Untreated transmitting mothers (n = 19) had significantly lower HIV-1 quasispecies diversity at delivery than untreated nontransmittting mothers (n = 18) (median Shannon entropy, 0.711 [0.642 to 0.816] versus 0.853 [0.762 to 0.925], P = 0.005). Eight mothers transmitted a single major env variant to their infants in utero, and one mother transmitted a single major env variant intrapartum. Four mothers transmitted multiple HIV-1 env variants to their infants in utero, and two mothers transmitted multiple env variants intrapartum. The remaining six intrapartum- and two in utero-infected infants had a homogeneous HIV-1 env quasispecies which did not comigrate with their mothers' bands at their first positive time point. In conclusion, in utero transmitters were more likely to transmit single or multiple major maternal viral variants. In contrast, intrapartum transmitters were more likely to transmit minor HIV-1 variants. These data indicate that different selective pressures, depending on the timing of transmission, may be involved in determining the pattern of maternal HIV-1 variant transmission.

Recovery of replication-competent virus from CD4 T cell reservoirs and change in coreceptor use in human immunodeficiency virus type 1-infected children responding to highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) suppresses plasma viremia in most patients with human immunodeficiency virus (HIV) infection. Prospective study of HIV-infected children (n=27) shows that, in 8 of 12 who responded to HAART (>/=0.5 log reduction in plasma HIV RNA), HAART restricted the number of coreceptors used by the predominant HIV isolate (mean number of coreceptors used at baseline was 4, vs. 1 coreceptor used at 6 months after treatment). This decrease was most striking in 6 of 8 children whose HIV coreceptor tropism changed from X4-tropic at baseline to R5-tropic. In 6 of 10 children tested, with plasma HIV RNA levels of <50 copies/mL, R5-tropic virus was isolated from CD4 T cell reservoirs. All the responding children had a significant increase in naive CD4 T cells (P<.05). These results show that persistent HIV T cell reservoirs are present in children and that HAART may influence the number and type of coreceptors used by the predominant virus isolate.

Presence of human immunodeficiency virus (HIV) type 1 and HIV-1-specific antibodies in cervicovaginal secretions of infected mothers and in the gastric aspirates of their infants.

The presence of human immunodeficiency virus (HIV) in cervicovaginal secretions (CVS) may be a risk factor for perinatal transmission. CVS of 25 women were evaluated for HIV and HIV mucosal antibodies; 16 infants had gastric aspirates cultured. Maternal plasma HIV was measured by quantitative RNA polymerase chain reaction. Seven women (28%), 4 of 19 pregnant and 3 of 7 nonpregnant, had HIV in CVS. Two of 4 HIV-infected neonates had positive gastric aspirate cultures. The 4 pregnant women with HIV in CVS did not transmit infection. HIV-specific secretory IgA was present in CVS of 10 (42%) of 24 women (in 3 cases concurrent with virus). Plasma HIV RNA levels at delivery were higher among transmitters (mean, 68,921 copies/mL) than nontransmitters (mean, 9457 copies/mL). Intermittent HIV shedding in CVS occurred despite mucosal antibodies and did not necessarily correlate with maternal plasma HIV RNA copy number. The presence of HIV in newborn gastric aspirates may be a risk factor for perinatal infection.

Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission. Effect of maternal zidovudine treatment on viral load.

OBJECTIVE: To determine if there are levels of human immunodeficiency virus type 1 (HIV-1) associated with a high or low risk of perinatal transmission and to ascertain the mechanism by which zidovudine treatment reduces perinatal transmission. DESIGN: A nonrandomized prospective cohort study. SETTING: University medical center and two general hospital affiliates from May 1989 to September 1994. PATIENTS: Ninety-two HIV-1-seropositive women (95 pregnancies) and their 97 infants. INTERVENTION: Forty-two mothers (43 pregnancies) received zidovudine therapy during pregnancy and/or during labor and delivery. Eleven infants received prophylactic zidovudine for the first 6 weeks after delivery. MAIN OUTCOME MEASURE: HIV-1 infection status of the infant. RESULTS: Twenty of the 97 infants were perinatally infected with HIV-1. Transmitting mothers were more likely to have plasma HIV-1 RNA levels higher than 50000 copies per milliliter at delivery than nontransmitting mothers (15 [75.0%] of 20 transmitters vs four [5.3%] of 75 nontransmitters; P < .001). None of the 63 women with less than 20000 HIV-1 RNA copies per milliliter transmitted. Twenty-two women treated with open-label oral zidovudine during gestation showed an eightfold median decrease in plasma RNA levels (median [25th and 75th percentile], 43043 [5699 and 63053] copies per milliliter before zidovudine vs 4238 [603 and 5116] HIV-1 RNA copies per milliliter at delivery; P < .001) and none transmitted. Four zidovudine-treated women with high HIV-1 levels transmitted despite the presence of zidovudine-sensitive virus in vitro in both the mothers and their infants. CONCLUSIONS: Maternal HIV-1 RNA levels were highly predictive of perinatal transmission risk and suggest that certain levels of virus late in gestation and/or during labor and delivery are associated with both a high risk and a low risk of transmission. Our results also suggest that zidovudine exerts a major protective effect by reducing maternal HIV-1 RNA levels prior to delivery and that further strategies are needed to prevent perinatal transmission in women with high or increasing virus levels and/or zidovudine-resistant virus.

Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study.

In a prospective study of factors associated with genital herpes simplex virus (HSV) type 2 transmission in couples in whom 1 partner had clinical genital HSV and the other did not, 11 (19%) of the 57 history-negative partners had HSV-2 antibody by Western blot at entry. In follow-up (mean, 16 months) of 29 HSV-2-seronegative partners, overall 4 (14%) seroconverted compared with 3 (23%) of 13 HSV-1- and -2-seronegative partners and 1 (6%) of 16 HSV-1-seropositive partners. Since all seroconverters were women, the risk of transmission may be higher in HSV-seronegative women. No significant differences were found between HSV-2-seronegative partners and seroconverters regarding duration of relationships, number of partner recurrences, intercourse frequency, or contraceptive method. However, 2 seroconverters were exposed to lesions without barrier contraception. This study suggests that infection is commonly asymptomatic and that although the overall risk of genital HSV transmission in couples is low (10%/year), the risk may be significantly increased in women and in seronegative individuals.

Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes.

OBJECTIVE: To determine the risk for genital herpes and asymptomatic herpes simplex virus (HSV) shedding in late pregnancy and delivery in a population of HSV type 2 (HSV-2)-seropositive but previously asymptomatic pregnant women. DESIGN: A prospective inception cohort study. PARTICIPANTS: A total of 1355 pregnant women with no history of genital herpes referred from three private obstetrics practices between November 1985 and June 1988. MAIN OUTCOME MEASURES: Confidential questionnaires evaluated sexual risk factors in relation to HSV-2 serologic status as determined by Western blot analysis. Herpes simplex virus shedding was determined by viral culture of the cervix and vulva and of any suspicious lesions. RESULTS: Antibody to HSV-2 was detected in 439 of 1355 pregnant women (32%) with no history of genital herpes. Asymptomatic HSV shedding was detected in 5 of 1160 cultures (0.43%) obtained in late pregnancy and during delivery. A first episode of clinical genital herpes was recognized by 43 of 264 HSV-2-seropositive women (16%) during their pregnancy. CONCLUSIONS: Serologic evidence of unknown HSV-2 infection was common in pregnant women without a history of genital herpes. Asymptomatic viral shedding in these women occurred at a rate similar to that seen in women with symptomatic genital HSV-2 infection. To improve recognition of genital herpes near term, obstetricians should counsel pregnant women about the high prevalence and mild and diverse symptoms of genital HSV-2 infection.

A prospective study of the effects of acyclovir treatment on the HSV-2 lymphoproliferative response of persons with frequently recurring HSV-2 genital infections.

In a randomized double-blinded fashion, herpes simplex virus type 2 specific lymphocyte proliferation (HSV-2-LP) was studied in patients with frequently recurring genital HSV-2 who were administered daily suppressive oral acyclovir (S-ACV) or placebo and acyclovir for 5 d (PLC/ACV) with recurrences. The pretreatment HSV-2-LP of subjects was low compared with that of controls with infrequently recurring genital HSV-2 (54,000 vs. 110,000 cpm). The HSV-2-LP increased with both S-ACV and PLC/ACV (101,000 and 94,000 cpm, respectively). After treatment was stopped, the HSV-2-LP decreased in both groups (59,000 cpm). Similar data were seen in a subpopulation given a second year of S-ACV. HSV recurrences were reduced in the S-ACV but not in the PLC/ACV group. These data suggest that a low HSV-2-LP in untreated patients is associated with frequent recurrences of genital HSV; a reduction of viral antigens by suppression with ACV or early treatment of HSV recurrences augments the HSV-2-LP response; and the recurrence pattern is not modulated by the HSV-2-LP response.

Human alpha-lymphoblastoid interferon. A phase I study including pharmacokinetics and effects on hematologic stem cells (CFU-GMs).

Human alpha lymphoblastoid interferon (Wellferon) was administered to 33 patients in a phase I study. Patients received Wellferon intramuscularly every 12 hours for 14 doses in nine dosage levels ranging from 0.75 X 10(6) units to 50.0 X 10(6) units. Toxicity tended to be dose dependent and included fever/chills, malaise, hematologic toxicity, and digestive tract toxicity. Thirty X 10(6) u q 12 h was felt to be the maximum tolerated dose. Three partial responses (renal cell carcinoma, diffuse histiocytic lymphoma, Hodgkin's disease) were achieved. Interferon rapidly (2 to 3 hours after the initial injection) reached peak serum levels which varied generally with dose and exceeded 500 u/ml at the 30 and 50 X 10(6) u dosages. Multiple doses of interferon resulted in cumulative peak levels substantially higher than first dose levels (greater than 500 u/ml at dosages greater than 3 X 10(6) u/ml and greater than 1,500 u/ml at dosages greater than or equal to 18 X 10(6) u). Interferon given at high dosages persisted up to 10 days beyond the final injection. Despite hematologic toxicity, inhibition of CFU-GM was not seen.

Comparison of Western Blot Analysis to microneutralization for the detection of type-specific herpes simplex virus antibodies.

A newly developed system (as described in the previous paper) employing separated herpes simplex virus (HSV) polypeptides electrophoretically transferred to nitrocellulose paper, Western Blot Analysis (WBA), was compared to microneutralization (MN) for the detection of type-specific antibody to HSV types 1 and 2 in 98 human sera. Sera containing HSV1-specific antibodies reacted at least twofold more densely (as quantitated by densitometric scanning) to HSV1 than HSV2 polypeptides, while sera with HSV2-specific antibodies reacted twofold more densely to HSV2 polypeptides. The reliability of this system was determined (1) by analysis of sera from patients with true primary herpes simplex infections, (2) by adsorption studies that removed cross-reacting antibodies, and (3) by comparison with neutralization. Of 36 sera found to have HSV1-type-specific antibody by WBA, 83% had MN ratios of less than 85 (indicating HSV1 antibody), while of 28 sera found to have HSV2-type-specific antibody by WBA, 89% had MN ratios of greater than 85 (indicating HSV2 antibodies). The MN ratio obtained on sera felt to have both HSV1-type-specific and HSV2-type-specific antibody by WBA ranged from 67 to 160. WBA agreed more closely with clinical isolates and adsorption studies than MN. This system not only accurately determines the HSV-type-specific antibody status of patients but provides important information on the specific immunogenic proteins.

Treatment of first episode genital HSV with oral acyclovir: long term follow-up of recurrences. A preliminary report.

Systemic acyclovir (ACV) treatment has been shown to have significant effects on shortening the clinical course of first episode genital HSV infections, decreasing the quantity of HSV antibody in convalescent phase serum, without affecting the incidence of recurrences in 6 months of follow-up. In order to assess long term recurrence patterns, we prospectively studied subjects enrolled in a randomized double blind trial of oral ACV for first episode genital HSV. Sixty-three of sixty-eight subjects were followed monthly for recurrences for a mean of 36 months with 90% of subjects completing two years. There was no difference in the incidence of recurrence (90%) in (29) placebo vs (37) ACV treated HSV-2 infected subjects. Recurrences rates were similar between ACV and placebo treated subjects with nonprimary HSV-2 infection followed 2 years. The majority of these subjects were found to have HSV-2 antibody in their acute sera suggesting prior asymptomatic acquisition of HSV-2 infection and therefore established ganglionic latency at the time of first clinical disease. In subjects with true primary HSV-2 infection, however, mean recurrence rates were significantly lower in ACV treated subjects after 6 months, 0.87 ACV vs 3 placebo per 6 month period (p less than 0.01). The percentage of subjects experiencing recurrences after 1 year was also reduced by ACV treatment (70% placebo subjects vs 12.5% ACV subjects).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell surface heterogeneity of human blood neutrophils and monocytes.

Until recently, human blood neutrophils (PMN) and monocytes have been considered to be homogeneous cell populations. However, much evidence has accumulated on their functional heterogeneity. This functional heterogeneity suggests the existence of different subsets of myeloid cells analogous to T and B subsets of lymphoid cells. The goal of this study was to investigate this question of myeloid subsets by examining myeloid cells for cell surface reactivity for IgG and complement (C). Normal PMN and monocytes were examined from 60 subjects for the presence of two types of IgG-Fc receptors and two activated C components, C3b and C3d. Most PMN and monocytes showed Fc receptor activity for rabbit IgG (Fc-R). In addition, the majority of monocytes but very few PMN reacted with human IgG (anti-Rh0) coated Rh-positive erythrocytes (Fc-H). Most PMN and monocytes showed C receptor reactivity for C3b, but only a minor subpopulation of both myeloid cells had C3d receptors. These data provide evidence that human blood myeloid cells may be composed of subsets with different membrane marker reactivities.

Immunological membrane markers of Hodgkin's cells.

Reed-Sternberg and other Hodgkin's giant cells derived from involved spleens and lymph nodes of patients with Hodgkin's disease were examined for surface markers of T and B cells and macrophages. Attachment and phagocytosis of untreated (E) or sensitized (EA and EAC) sheep red blood cells and yeast by Reed-Sternberg cells did not occur. IgG frequently detected at the membrane of Reed-Sternberg cells was partially removed by incubation and washing at 37 degrees C. Fluorescence with a specific anti-T cell serum was not seen on Reed-Sternberg and other Hodgkin's giant cells lack most detectable normal human lymphoid cell markers, but do exhibit membrane bound immunoglobulin possibly of exogenous origin.