Lower Plasma Viremia Research Articles

Control of Simian Immunodeficiency Virus Infection in Prophylactically Vaccinated, Antiretroviral Treatment-Naive Macaques Is Required for the Most Efficacious CD8 T Cell Response during Treatment with the Interleukin-15 Superagonist N-803.

The IL-15 superagonist N-803 has been shown to enhance the function of CD8 T cells and NK cells. We previously found that in a subset of vaccinated, ART-naive, SIV+ rhesus macaques, N-803 treatment led to a rapid but transient decline in plasma viremia that positively correlated with an increase in the frequency of CD8 T cells. Here, we tested the hypothesis that prophylactic vaccination was required for the N-803 mediated suppression of SIV plasma viremia. We either vaccinated rhesus macaques with a DNA prime/Ad5 boost regimen using vectors expressing SIVmac239 gag with or without a plasmid expressing IL-12 or left them unvaccinated. The animals were then intravenously infected with SIVmac239M. 6 months after infection, the animals were treated with N-803. We found no differences in the control of plasma viremia during N-803 treatment between vaccinated and unvaccinated macaques. Interestingly, when we divided the SIV+ animals based on their plasma viral load set-points prior to the N-803 treatment, N-803 increased the frequency of SIV-specific T cells expressing ki-67+ and granzyme B+ in animals with low plasma viremia (<104 copies/mL; SIV controllers) compared to animals with high plasma viremia (>104 copies/mL; SIV noncontrollers). In addition, Gag-specific CD8 T cells from the SIV+ controllers had a greater increase in CD8+CD107a+ T cells in ex vivo functional assays than did the SIV+ noncontrollers. Overall, our results indicate that N-803 is most effective in SIV+ animals with a preexisting immunological ability to control SIV replication. IMPORTANCE N-803 is a drug that boosts the immune cells involved in combating HIV/SIV infection. Here, we found that in SIV+ rhesus macaques that were not on antiretroviral therapy, N-803 increased the proliferation and potential capacity for killing of the SIV-specific immune cells to a greater degree in animals that spontaneously controlled SIV than in animals that did not control SIV. Understanding the mechanism of how N-803 might function differently in individuals that control HIV/SIV (for example, individuals on antiretroviral therapy or spontaneous controllers) compared to settings where HIV/SIV are not controlled, could impact the efficacy of N-803 utilization in the field of HIV cure.

Interferon Alpha-Inducible Protein 27 Expression Is Linked to Disease Severity in Chronic Infection of Both HIV-1 and HIV-2

Disease progression is slower in HIV-2, as compared with HIV-1 infection, in accordance with low or undetectable plasma viremia at viral setpoint. However, it is unclear why most HIV-2 infected individuals are still at risk of developing AIDS. To explore if specific host responses are linked to HIV disease severity, we have compared blood gene expression profiles between HIV seronegative and HIV-1, HIV-2 or dually HIV-1/HIV-2 infected individuals. In this study the gene encoding Interferon alpha-inducible protein 27 (IFI27) was found to be the most differentially expressed. Detailed expression analysis revealed significantly higher IFI27 expression in HIV infected individuals compared with seronegative individuals, irrespectively of HIV type. Moreover, IFI27 expression was higher in HIV-1 than in HIV-2 infected individuals. Multiple linear regression analysis, adjusting for age and sex, showed also that plasma viral load was the strongest predictor of IFI27 expression, followed by CD4% and HIV type. In line with this, IFI27 expression was found to be higher in HIV-2 viremic, compared with HIV-2 aviremic individuals. Still, HIV-2 aviremic individuals displayed elevated IFI27 expression compared with seronegative individuals. Furthermore, in HIV-2 infected individuals, IFI27 expression was also correlated with plasma markers previously linked to inflammation and disease progression in HIV infection. Taken together, our findings suggest that sustained elevation of type I interferon signaling, here reflected by elevated IFI27 expression in the chronic infection phase, is a key pathogenic feature of both HIV-1 and HIV-2.

Virologic and Immunologic Features of Simian Immunodeficiency Virus Control Post-ART Interruption in Rhesus Macaques.

Antiretroviral therapy (ART) cannot eradicate human immunodeficiency virus (HIV) and a rapid rebound of virus replication follows analytical treatment interruption (ATI) in the vast majority of HIV-infected individuals. Sustained control of HIV replication without ART has been documented in a subset of individuals, defined as posttreatment controllers (PTCs). The key determinants of post-ART viral control remain largely unclear. Here, we identified 7 SIVmac239-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7 months, and controlled plasma viremia at <104 copies/ml for up to 8 months after ATI and <200 copies/ml at the latest time point. We characterized immunologic and virologic features associated with post-ART SIV control in blood, lymph node (LN), and colorectal (RB) biopsy samples compared to 15 noncontroller (NC) RMs. Before ART initiation, PTCs had higher CD4 T cell counts, lower plasma viremia, and SIV-DNA content in blood and LN compared to NCs, but had similar CD8 T cell function. While levels of intestinal CD4 T cells were similar, PTCs had higher frequencies of Th17 cells. On ART, PTCs had significantly lower levels of residual plasma viremia and SIV-DNA content in blood and tissues. After ATI, SIV-DNA content rapidly increased in NCs, while it remained stable or even decreased in PTCs. Finally, PTCs showed immunologic benefits of viral control after ATI, including higher CD4 T cell levels and reduced immune activation. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.IMPORTANCE While effective, antiretroviral therapy is not a cure for HIV infection. Therefore, there is great interest in achieving viral remission in the absence of antiretroviral therapy. Posttreatment controllers represent a small subset of individuals who are able to control HIV after cessation of antiretroviral therapy, but characteristics associated with these individuals have been largely limited to peripheral blood analysis. Here, we identified 7 SIV-infected rhesus macaques that mirrored the human posttreatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from noncontrollers. Lower viral burden and preservation of immune homeostasis, including intestinal Th17 cells, both before and after ART, were shown to be two major factors associated with the ability to achieve posttreatment control. Overall, these results move the field further toward understanding of important characteristics of viral control in the absence of antiretroviral therapy.

Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants

Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8+ T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML180–188) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.

Nef Proteins from HIV-1 Elite Controllers Are Inefficient at Preventing Antibody-Dependent Cellular Cytotoxicity

Impairment of Nef function, including reduced CD4 downregulation, was described in a subset of HIV-1-infected individuals that control viral replication without antiretroviral treatment (elite controllers [EC]). Elimination of HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) requires the presence of envelope glycoproteins (Env) in the CD4-bound conformation, raising the possibility that accumulating CD4 at the surface of virus-infected cells in EC could interact with Env and thereby sensitize these cells to ADCC. We observed a significant increase in the exposure of Env epitopes targeted by ADCC-mediating antibodies at the surface of cells expressing Nef isolates from EC; this correlated with enhanced susceptibility to ADCC. Altogether, our results suggest that enhanced susceptibility of HIV-1-infected cells to ADCC may contribute to the EC phenotype. Nef clones derived from elite controllers (EC) have been shown to be attenuated for CD4 downregulation; how this contributes to the nonprogressor phenotype of these infected individuals remains uncertain. Increasing evidence supports a role for HIV-specific antibody-dependent cellular cytotoxicity (ADCC) in controlling viral infection and replication. Here, we show that residual CD4 left at the surface of cells expressing Nef proteins isolated from ECs are sufficient to allow Env-CD4 interaction, leading to increased exposure of Env CD4-induced epitopes and increased susceptibility of infected cells to ADCC. Our results suggest that ADCC might be an active immune mechanism in EC that helps to maintain durable suppression of viral replication and low plasma viremia level in this rare subset of infected individuals. Therefore, targeting Nef's ability to downregulate CD4 could render HIV-1-infected cells susceptible to ADCC and thus have therapeutic utility.

Efficacy of genotypic drug resistance testing in patients with low-level plasma HIV-1 viremia

BackgroundDrug resistance is common at low HIV viral loads and often requires modification of antiretroviral treatment, however commercial genotyping platforms are optimized for viremia >2000copies/ml. Our aim was to analyze the results of drug resistance genotyping in samples with viral load <2000copies/ml. FindingsResistance testing was performed using combined commercial (Viroseq 2.8) and in-house bulk sequencing methodology in 18 treatment naive and 45 antiretroviral treated patients (in total 71 samples were analyzed). Drug resistance was evaluated based on the International AIDS Society-USA 2013 update. Sequencing success rate and drug resistance patterns were evaluated.Overall sequencing success rate was 87.4%. In viremia range of 50–1000copies/ml 86.6% samples were successfully sequenced with 75.0% for levels of 50–200copies/ml, 90.5% for 201–500copies/ml, 91.7% for 501–1000copies/ml and 88.46% for 1001–2000copies/ml. Drug resistance mutations were found in 43.5% sequences, the overall resistance prevalence for NRTI was 30.65%, for NNRI: 19.35% and 11.29% for PI. In treatment naive patients 31.25% sequences with drug resistance mutations were found, among antiretroviral treatment failing patients in 52.17% samples. Across viremia ranges resistance was observed in 55.6% sequences for 50–200copies/ml, 36.84% for 201–500copies/ml and 36.36% for 501–1000copies/ml and 47.83% for 1001–2000copies/ml. ConclusionsSuccess rate for genotyping at low plasma viremia levels is high and allows to guide treatment optimization. As drug resistance is commonly found at low viral loads, genotyping should be attempted in every virologically failing patient regardless the plasma viremia.

Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication

Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy. We measured the size of HIV reservoirs in CD4(+) T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy. We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART. Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.

FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−γC−/− mice in vivo

AbstractThe role of FoxP3+CD4+ regulatory T (Treg) cells in HIV-1 disease in vivo is poorly understood due to the lack of a robust model. We report here that CD4+FoxP3+ T cells are developed in all lymphoid organs in humanized Rag2−/−γC−/− (DKO-hu HSC) mice and they display both Treg phenotype and Treg function. These FoxP3+ Treg cells are preferentially infected and depleted by a pathogenic HIV-1 isolate in HIV-infected DKO-hu HSC mice; and depletion of Treg cells is correlated with induction of their apoptosis in vivo. When CD4+CD25+/hi Treg cells are depleted with the IL-2–toxin fusion protein (denileukin diftitox), HIV-1 infection is significantly impaired. This is demonstrated by reduced levels of productively infected cells in lymphoid organs and lower plasma viremia. Therefore, FoxP3+ Treg cells are productively infected and play an important role in acute HIV-1 infection in vivo. The DKO-hu HSC mouse will be a valuable model to study human Treg functions and their role in HIV-1 pathogenesis in vivo.

Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV‐specific CD8+ T cells

A better control of viral replication in long-term non-progressors has been associated with polyfunctional CD8(+) T cell responses. However, low levels of HIV replication could be the cause rather than the consequence of enhanced immune responses in long-term non-progressors. The functional profile and the expansion ability of HIV-Gag- and HIV-Nef-specific CD8 responses were analysed measuring the production of MIP-1beta, IL-2, TNF-alpha and expression of CD107, using polychromatic flow cytometry, in 36 HIV-infected patients at baseline and after 12 months of highly active antiretroviral therapy (HAART) and complete viral suppression. Most patients presented detectable Gag and Nef responses both at baseline and after 1 year of HAART, with a significant decline after achieving viral suppression. At baseline, the majority of CD8(+) response was due to cells producing only MIP-1beta or simultaneously MIP-1beta and CD107. The functional profile did not significantly change after achieving complete viral suppression with HAART. Therefore, control of HIV-1 replication after 1 year of HAART had no significant impact on the quality of HIV-1-specific CD8 response, but the effects of treatment in long-term, or of early HAART are not known. Thus, it is still uncertain whether multifunctional CD8 responses are the cause or consequence of low plasma viremia.

HIV-1-Specific T Cell Precursors with High Proliferative Capacity Correlate with Low Viremia and High CD4 Counts in Untreated Individuals

Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-gamma ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells. To determine which responses correlate with viral suppression and positive immunologic outcome, PBMC from 32 chronically untreated HIV-1-infected individuals were evaluated in response to peptide pools, representing the complete HIV-1 Gag, Nef, and Rev proteins, by PHPC and IFN-gamma ELISPOT assay, which instead identifies effector T cells with low proliferative capacity. High magnitude of Gag-specific PHPC, but not ELISPOT, responses significantly correlated with low plasma viremia, due to responses directed toward p17 and p15 subunits. Only Gag p17-specific PHPC response significantly correlated with high CD4 counts. Analysis of 20 additional PBMC samples from an independent cohort of chronically untreated HIV-1-infected individuals confirmed the correlation between Gag p17-specific PHPC response and either plasma viremia (inverse correlation) or CD4 counts (direct correlation). Our results indicate that the PHPC assay is quantitatively and qualitatively different from the ELISPOT assay, supporting that different T cell populations are being evaluated. The PHPC assay might be an attractive option for individual patient management and for the design and testing of therapeutic and prophylactic vaccines.

Patterns of CD8+Immunodominance May Influence the Ability ofMamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication

Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of human immunodeficiency virus and simian immunodeficiency virus (SIV). CD8(+) T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8(+) T cells contribute to control of viral replication should yield important insights for vaccine design. We have recently identified an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with the pathogenic isolate SIVmac239. Here, we infected four Mamu-B*08-positive macaques with SIVmac239 to investigate why some of these macaques control viral replication. Three of the four macaques controlled SIVmac239 replication with plasma virus concentrations below 20,000 viral RNA copies/ml at 20 weeks postinfection; two of four macaques were elite controllers (ECs). Interestingly, two of the four macaques preserved their CD4(+) memory T lymphocytes during peak viremia, and all four recovered their CD4(+) memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8(+) T-cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Additionally, the ECs mounted strong and broad CD8(+) T-cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8(+) T cells accounted for the majority of mutations in the virus at 18 weeks postinfection. Interestingly, patterns of viral variation in Nef differed between the ECs and the other two macaques. Natural containment of AIDS virus replication in Mamu-B*08-positive macaques may, therefore, be related to a combination of immunodominance and viral escape from CD8(+) T-cell responses.

Co-expression of Apoptosis-Related Molecules on Activated CD8+ CD38+ T-cells is Associated with HIV-1 Disease Progression

CD8+ T cells play a major role in controlling HIV-1 infection through the release of soluble lytic and non-lytic antiviral factors. Their decrease or defective function contributes to the HIV-1 disease progression. HIV-1 disease progression has been associated with a remarkable increase of CD38 expression on CD8+ T-cells. It has been also documented that a significant distribution of HIV-specific CD8+T-cells resides in the CD8+CD38+ T-cell sub-population. The failure of HIV-specific CD8+CD38+ T-cells to control HIV-1 infection has been attributed to several mechanisms including apoptosis. However, the relationship between the CD38 expression and molecular events involved in CD8+ T-cell apoptosis is not well understood. Using four-color flow cytometric analysis, the present cross-sectional study we evaluated the expression of four membrane-associated apoptosis-related molecules (TNFR-1, Annexin-V, CXCR4, and CD95) and two cytoplasm-associated apoptosis-related molecules (Bcl-2 and the active form caspase-3) in 41 HIV-1 positive patients and 15 HIV-1 negative individuals. Flow cytometric analysis made on freshly isolated PBMC showed that HIV-1 infection alters the level of expression of CD38, CD95, CXCR4, Bcl-2 and active caspase-3. No significant change in the expression of Annexin V or TNFR-1 was found. A positive correlation was established between CD95, CXCR4, and active caspase-3 expression with low CD4 count and high plasma viremia and CD38 expression. Data suggest that the majority of activated CD8+CD38+ T-cells were apoptotic because they expressed active caspase-3 and the rest of these cells were highly susceptible to become apoptotic since they co-expressed CD95 and CXCR4. Results also suggest that one of the most likely HIV-mediated apoptosis mechanisms is via CD95 and CXCR4 induction through the caspase cascade despite the expression of Bcl-2. All these observations may provide an additional explanation of why HIV-1 infection is not fully contained by HIV-specific CD8+CD38+ T-cells leading to HIV-1 disease progression.

Co-expression of apoptosis-related molecules on activated CD8+CD38+ T-cells is associated with HIV-1 disease progression (B213)

Abstract HIV-1 disease progression has been associated with a remarkable increase of CD8+CD38+ T-cells. It has been documented that a significant distribution of HIV-specific CD8+ T-cells resides in the CD8+CD38+ T-cell sub-population. The failure of HIV-specific CD8+CD38+ T-cells to control HIV-1 infection has been attributed to several mechanisms including apoptosis. However, the relationship between the CD38 expression and molecular events involved in CD8+ T-cell apoptosis is not well understood. We evaluated the expression of two membrane-associated apoptosis-related molecules: CXCR4 and CD95, and two cytoplasm-associated apoptosis-related molecules: Bcl-2 and active caspase-3 in 41 HIV-1 positive patients and 15 HIV-1 negative individuals. HIV-1 infection alters the level of expression of CD38, CD95, CXCR4, Bcl-2, and active caspase-3. A positive correlation was established between CD95, CXCR4, and active caspase-3 expression with low CD4 count and high plasma viremia and CD38 expression. The majority of activated CD8+CD38+ T-cells were apoptotic since they expressed active caspase-3 and the rest of these cells were susceptible to become apoptotic since they co-expressed CD95 and CXCR4. We suggest that one of the most likely HIV-mediated apoptosis mechanisms is via CD95 and CXCR4 induction through the caspase cascade despite Bcl-2 expression. This provides another explanation of why HIV-1 infection is not fully contained by HIV-specific CD8+CD38+ T-cells. Supported by NIH/RCMI Grant # G12-RR03035.

Comparison of Human Immunodeficiency Virus (HIV)-Specific T-Cell Responses in HIV-1- and HIV-2-Infected Individuals in Senegal

Human immunodeficiency virus type 2 (HIV-2) infection is typically less virulent than HIV-1 infection, which may permit the host to mount more effective, sustained T-cell immunity. We investigated antiviral gamma interferon-secreting T-cell responses by an ex vivo Elispot assay in 68 HIV-1- and 55 HIV-2-infected Senegalese patients to determine if differences relate to more efficient HIV-2 control. Homologous HIV-specific T cells were detected in similar frequencies (79% versus 76%, P = 0.7) and magnitude (3.12 versus 3.08 log(10) spot-forming cells/10(6) peripheral blood mononuclear cells) in HIV-1 and HIV-2 infection, respectively. Gag-specific responses predominated in both groups (>/=64%), and significantly higher Nef-specific responses occurred in HIV-1-infected (54%) than HIV-2-infected patients (22%) (P < 0.001). Heterologous responses were more frequent in HIV-1 than in HIV-2 infection (46% versus 27%, P = 0.04), but the mean magnitude was similar. Total frequencies of HIV-specific responses in both groups did not correlate with plasma viral load and CD4(+) T-cell count in multivariate regression analyses. However, the magnitude of HIV-2 Gag-specific responses was significantly associated with lower plasma viremia in HIV-1-infected patients (P = 0.04). CD4(+) T-helper responses, primarily recognizing HIV-2 Gag, were detected in 48% of HIV-2-infected compared to only 8% of HIV-1-infected patients. These findings indicate that improved control of HIV-2 infection may relate to the contribution of T-helper cell responses. By contrast, the superior control of HIV-1 replication associated with HIV-2 Gag responses suggests that these may represent cross-reactive, higher-avidity T cells targeting epitopes within Gag regions of functional importance in HIV replication.

Frequency of a Mutated CCR-5 Allele (Delta32) among Italian Healthy Donors and Individuals at Risk of Parenteral HIV Infection

The aim of this study was to assess the frequency of a truncated allele of the CCR-5 gene (delta32) in Italy, and address its possible role in parenteral HIV transmission, as well as its influence in HIV-associated disease progression. In 371 unrelated seronegative healthy blood donors the delta32 allele frequency was 0.047; this figure was significantly different from those reported in northern America and northern Europe populations. However, delta32 allele frequency in healthy individuals did not differ significantly from that found in 54 seronegative drug users (0.065), 98 seronegative hemophiliacs (0.051), and 81 seropositive hemophiliacs (0.049). Although in seropositive hemophiliacs the wt/delta32 heterozygous genotype was associated with a trend to a slower decline in CD4+ cell counts, its presence did not seem to influence disease progression, as comparable delta32 allele frequency frequencies were found among progressing (0.042) and nonprogressing (0.111) patients. These data do not seem to support a protective role of the delta32 allele in preventing HIV infection through the parenteral route, or in influencing the natural history of the disease in this particular risk category, although the delta32 heterozygous state was associated with lower plasma viremia levels. On the other hand, the finding of non-syncytium-inducing HIV strains in the majority of delta32 heterozygous seropositive patients suggests that its presence could not be a major factor in driving a switch toward more cytopathic, T-tropic HIV strains through selective pressure in coreceptor usage.

Chemokine-independent in vitro resistance to human immunodeficiency virus (HIV-1) correlating with low viremia in long-term and recently infected HIV-1-positive persons.

Chemokines have been implicated as protective factors against human immunodeficiency virus (HIV) infection, competing for binding to receptors that also function as coreceptors for HIV. In this study of HIV-positive donors, peripheral blood mononuclear cell (PBMC) culture resistance to endogenous and exogenous HIV correlated with low plasma viremia and high in vitro RANTES production. However, resistant cells were not rendered susceptible by neutralization of C-C chemokines, and addition of C-C chemokines did not consistently suppress endogenous virus or exogenous HIV-1MN. In contrast, CD8 T cell depletion markedly decreased the frequency of resistant cultures without reducing C-C chemokine production. Among newly infected persons, half exhibited phenotype switching from preinfection susceptibility to postinfection resistance, suggesting that genetically predetermined constitutive cytokine production or allelic receptor expression are not generally responsible for in vitro resistance and nonprogression.

Long-term resistance to HIV infection in vertical HIV infection: cytokine production, HIV isolation, and HIV phenotype define long-term resistant hosts.

We analyzed immunologic (CD4 and CD8 slopes; interferon-gamma, interleukin-2, interleukin-10, and chemokines production; concentration of IgE; beta 2-microglobulin) and virologic (p24; HIV isolability and phenotype; plasma viremia) parameters in HIV vertically infected children > or = 8 years of age without disease progression or mild symptoms and an absolute CD4+ count > or = 500/microliter with CD4+ percentage > or = 25%. The results were compared to those of two control groups: (1) slow progressors, children > or = 8 years of age with moderate symptomatology and/or moderate CD4 depletion, and (2) progressors, children > or = 8 years of age with severe clinical disease and/or severe CD4 depletion. Pediatric long-term resistant hosts were characterized by higher production of interleukin-2 and interferon-gamma and lower production of interleukin-10, normal concentration of IgE, HIV isolates with a non-syncytium-inducing phenotype, and lower plasma viremia. This condition was not associated with the concentration of beta 2-microglobulin, p24, and chemokines, or with HIV isolability. The IL-10/IL-2 ratio best correlated with both CD4 counts and disease progression. Thus, vertically infected children showing resistance to disease progression are immunologically and virologically distinct from those in whom progressive HIV infection is observed.