Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens

BACKGROUND & AIMS: Professional antigen-presenting dendritic cells are capable of eliciting a vigorous antiviral response in naive T cells. The administration of antigen-loaded dendritic cells offers a potential approach to induce high-level immunity against hepatitis C virus. METHODS: The dendritic cell population in mice was expanded in vivo by hydrodynamic delivery of naked DNA that encoded the secreted form of human fms-like tyrosine kinase 3 ligand. The CD11c-enriched dendritic cell population obtained from the spleen was transduced in vitro with recombinant hepatitis C virus core and nonstructural 5 proteins by using macromolecular-based protein delivery. Vaccine efficacy was assessed with a cytotoxic T-lymphocyte assay, cytokine enzyme-linked immunosorbent assays, and intracellular cytokine staining in vitro and by a tumor challenge model in vivo. RESULTS: Relative to mice inoculated with nontransduced dendritic cells, splenocytes derived from mice immunized with either hepatitis C virus core-transduced or nonstructural 5-transduced dendritic cells showed 3- to 5-fold greater antigen-specific cytotoxic T lymphocyte activity. The CD4(+) T cells obtained from mice immunized with nonstructural 5-transduced dendritic cells produced interferon gamma, but not interleukin 4, when stimulated with nonstructural 5. In contrast, T cells derived from mice immunized with hepatitis C virus core-transduced dendritic cells produced neither interferon gamma nor interleukin 4 when stimulated with core protein. Mice vaccinated with nonstructural 5-transduced dendritic cells, but not a nonstructural 5-expressing plasmid, showed a sustained antiviral response to nonstructural 5 as evidenced by reduced growth of nonstructural 5-expressing tumor cells inoculated 10 weeks after vaccination. CONCLUSIONS: These findings suggest that vaccination with protein-transduced dendritic cells may constitute an important antiviral strategy for hepatitis C virus.     

Current concepts of HIV transmission

The epithelial surface acts as an effective barrier against HIV. The various mucosal surfaces possess specific mechanisms that help prevent the transmission of virus. Yet, HIV manages to cross these barriers to establish infection, and this is enhanced in the presence of physical trauma or preexisting sexually transmitted infections. Once breached, the virus accesses numerous cells such as dendritic cells, T cells, and macrophages present in the underlying epithelia. Although these cells should contribute to innate and adaptive immunity to infection, they also serve as permissive targets to HIV and help in the initiation and dissemination of infection. Understanding how the various mucosal surfaces, and the cells within them, respond to the presence of HIV is essential in the design of therapeutic agents that will help to prevent HIV transmission.     

Modification of the immune response against hepatitis B virus by the human immunodeficiency virus

Summary Hepatitis B virus and the human immunodeficiency virus are similarly transmitted. Individuals with preexisting HIV infection have a higher chance to become HBsAg carriers than do anti-HIV negative persons. Cytotoxic T cells with specificity for HBcAg, that are under the control of HBcAg-specific helper T cells, are responsible for liver injury. There is good evidence that HIV infection lowers inflammatory activity, is associated with milder liver histology, high levels of viral replication and low seroconversion rates. In addition interferon alpha therapy is less effective in anti-HIV positive subjects. The immune response against HBsAg is helper T-cell dependent and vaccination against hepatitis B is of low effectiveness. In addition, vaccination against hepatitis B may activate the HIV disease and is, therefore, presently not to be recommended.     

Immune responses in hepatitis C virus infection and mechanisms of hepatitis C virus persistence

Immune responses against hepatitis C virus (HCV) play a crucial role in the pathogenesis of chronic hepatitis C. HCV infection often persists and leads to chronic hepatitis and eventually cirrhosis. Accumulated data suggest that HCV proteins suppress host immune responses through the suppression of functions of immune cells, such as cytotoxic T lymphocytes, natural killer cells, and dendritic cells. They also suppress the type 1 interferon signaling system. The resulting insufficient immune responses against HCV lead to the sustained infection. The appropriate control of immune responses would contribute to the eradication of HCV and the improvement of hepatitis, but there are still many issues to be clarified. This review describes the scientific evidence to support these emerging concepts, and will touch on the implications for improving antiviral therapy.     

Impaired TRAIL-dependent cytotoxicity of CD1c-positive dendritic cells in chronic hepatitis C virus infection

Dendritic cells (DCs) play a central role in antiviral immunity. Conflicting data on DC function have been reported for hepatitis C virus (HCV) infection. In addition to antigen presentation and cytokine secretion, a subset of human DCs displays direct cytotoxic activity. It has been suggested that measles virus and human immunodeficiency virus (HIV) may enhance cytotoxicity of DCs potentially leading to apoptosis of activated T cells and subsequent down-regulation of antiviral immune responses. We demonstrate that CD1c-positive myeloid DCs, but not BDCA-4-positive plasmacytoid DCs, are able to kill different target cells mainly via tumour necrosis factor-related apoptosis-inducing ligand. The ability of CD1c+ DCs to lyze target cells was found to be completely impaired in patients with chronic hepatitis C (10 chronic HCV patients vs 10 healthy controls; P < 0.001) but not in patients with primary biliary cirrhosis. Successful antiviral therapy of chronic hepatitis C rescued the cytotoxicity of DCs. Myeloid DCs of HCV patients and healthy controls had a similar phenotype and endocytotic activity, however, the frequency of mDCs in the peripheral blood was lower (P = 0.004) and the allostimulatory function was weaker (P < 0.001) in chronic hepatitis C. Thus, in contrast to HIV and measles virus studies on monocyte-derived DCs, freshly isolated myeloid DCs of patients with hepatitis C do not show an increased but a completely abolished cytotoxic activity. The impaired DC cytotoxicity could represent a novel mechanism for the increased prevalence of autoimmunity in HCV infection.     

Human immunodeficiency virus interactions with CD8+ T lymphocytes

Human immunodeficiency virus (HIV)-specific CD8+ T cells can mediate anti-HIV activity by both cytolytic (cytotoxic T lymphocyte or CTL) and non-cytolytic mechanisms (antiviral) and play a crucial role in HIV pathogenesis. Both mechanisms actively contribute to the control of HIV in vivo. The non-cytolytic CD8+T cells from individuals infected with HIV suppress virus replication in CD4+ T cells in vitro by a non-cytolytic mechanism that involves interplay of several chemokines and an unidentified secreted soluble CD8 (+)-cell antiviral factor (CAF). There is immense value of these two distinct CD8 activities in anti-HIV responses and their necessity to be maintained during highly active antiretroviral therapy (HAART). The aim of this review is to provide an overview of some of the novel aspects of CD8+ T cell interactions with HIV, their role in HIV pathogenesis, HAART therapy, HIV disease progression, gene expression and interactions with other cell types during HIV infection.     

Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice

The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4(+) Foxp3(+) regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. Conclusion: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. (HEPATOLOGY 2012;56:873-883).     

A virocidal amphipathic {alpha}-helical peptide that inhibits hepatitis C virus infection in vitro

An amphipathic alpha-helical peptide (C5A) derived from the membrane anchor domain of the hepatitis C virus (HCV) NS5A protein is virocidal for HCV at submicromolar concentrations in vitro. C5A prevents de novo HCV infection and suppresses ongoing infection by inactivating both extra- and intracellular infectious particles, and it is nontoxic in vitro and in vivo at doses at least 100-fold higher than required for antiviral activity. Mutational analysis indicates that C5A's amphipathic alpha-helical structure is necessary but not sufficient for its virocidal activity, which depends on its amino acid composition but not its primary sequence or chirality. In addition to HCV, C5A inhibits infection by selected flaviviruses, paramyxoviruses, and HIV. These results suggest a model in which C5A destabilizes viral membranes based on their lipid composition, offering a unique therapeutic approach to HCV and other viral infections.     

Hepatitis C virus eradication associated with hepatitis B virus superinfection and development of a hepatitis B virus specific T cell response

BACKGROUND/AIMS: Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic hepatitis C that eventually lead to clearance of both viruses are completely unknown. METHODS: We analyzed the virus specific CD4+ and CD8+ T cell response during an acute HBV superinfection in a patient with chronic hepatitis C. RESULTS: The patient eliminated hepatitis C virus (HCV)-RNA and HBV-DNA from serum soon after the clinical onset of acute hepatitis B. The HBV specific T cell response found in this patient corresponds to the typical response that has been described in acute hepatitis B without chronic HCV infection. In contrast the hepatitis C specific immune response was similar to that generally found in chronic hepatitis C despite the fact that the patient also eliminated HCV-RNA. CONCLUSIONS: We hypothesize that the acute HBV infection induced a HBV specific T cell response which was associated with elimination HBV DNA and HCV-RNA, the latter possibly by bystander mechanisms, e.g. via secretion of cytokines. If such a non-specific bystander mechanism which has proven to be effective in the experimental setting and which is formally described here for a single patient can be shown to be a more general phenomenon, it may support the approach with new antiviral strategies, e.g. the induction of non-specific defense mechanisms against HCV.     

Polyunsaturated liposomes are antiviral against hepatitis B and C viruses and HIV by decreasing cholesterol levels in infected cells

The pressing need for broad-spectrum antivirals could be met by targeting host rather than viral processes. Cholesterol biosynthesis within the infected cell is one promising target for a large number of viral systems, including hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV. Liposomes developed for intracellular, endoplasmic reticulum (ER)-targeted in vivo drug delivery have been modified to include polyunsaturated fatty acids that exert an independent antiviral activity through the reduction of cellular cholesterol. These polyunsaturated ER liposomes (PERLs) have greater activity than lovastatin (Mevacor, Altoprev), which is clinically approved for lowering cholesterol and preventing cardiovascular disease. Treatment of HCV, HBV, and HIV infections with PERLs significantly decreased viral secretion and infectivity, and pretreatment of naïve cells reduced the ability of both HCV and HIV to establish infections because of the decreased levels of plasma membrane cholesterol. Direct competition for cellular receptors was an added effect of PERLs against HCV infections. The greatest antiviral activity in all three systems was the inhibition of viral infectivity through the reduction of virus-associated cholesterol. Our study demonstrates that PERLs are a broadly effective antiviral therapy and should be developed further in combination with encapsulated drug mixtures for enhanced in vivo efficacy.     

HIV Infection and Spread between Th17 Cells

HIV mainly targets CD4⁺ T cells, from which Th₁₇ cells represent a major cell type, permissive, and are capable of supporting intracellular replication at mucosal sites. Th₁₇ cells possess well-described dual roles, while being central to maintaining gut integrity, these may induce inflammation and contribute to autoimmune disorders; however, Th₁₇ cells’ antiviral function in HIV infection is not completely understood. Th₁₇ cells are star players to HIV-1 pathogenesis and a potential target to prevent or decrease HIV transmission. HIV-1 can be spread among permissive cells via direct cell-to-cell and/or cell-free infection. The debate on which mode of transmission is more efficient is still ongoing without a concrete conclusion yet. Most assessments of virus transmission analyzing either cell-to-cell or cell-free modes use in vitro systems; however, the actual interactions and conditions in vivo are not fully understood. The fact that infected breast milk, semen, and vaginal secretions contain a mix of both cell-free viral particles and infected cells presents an argument for the probability of HIV taking advantage of both modes of transmission to spread. Here, we review important insights and recent findings about the role of Th₁₇ cells during HIV pathogenesis in mucosal surfaces, and the mechanisms of HIV-1 infection spread among T cells in tissues.     

Impact of human immune deficiency virus infection on hepatitis C virus infection and replication

Human immune deficiency virus (HIV) and human hepatitis C virus (HCV) infection are frequent in patients who have been exposed to blood or blood-derived products. It has been suggested that HIV infection increases HCV replication altering the course of HCV-related disease. However, it is not known if HIV directly enhances HCV replication or if its effect is the consequence of HIV infection of other cell types that control HCV replication (lymphocytes, macrophages). While the main cell targets for HIV infection are mononuclear leukocytes bearing CD4 and the chemokine receptors CCR5 and CXCR4, HCV was originally thought to be strictly hepatotropic, but it is now known that HCV can also replicate in peripheral blood mononuclear cells (PBMC). Therefore, in co-infected individuals, these two different viruses could share cell targets and interact either directly or indirectly. Some membrane receptors can be used by both HCV and HIV for entry into target cells, but the intracellular mechanisms shared by these viruses are not known. Lack of experimental systems providing suitable methods for the study of HCV replication in the presence or absence of HIV co-infection has hampered advances in this research area, but recent investigations are currently going on in order to answer these questions. This is an important issue, as knowledge of HIV/HCV interactions is required for the design of effective antiviral therapies.     

Hepatitis B and C virus infections in the immune compromised

PURPOSE OF REVIEW: This review compares and contrasts the natural history and treatment of hepatitis B and C virus infections in three principal populations of immune compromised individuals: (1) patients co-infected with HIV; (2) patients with liver failure secondary to hepatitis B or C virus infection who undergo liver transplantation, and (3) patients with hepatitis B or C virus infection who undergo anticancer chemotherapy. RECENT FINDINGS: Chronic liver disease resulting from hepatitis B or C virus infection progresses more rapidly in patients co-infected with HIV than in HIV negative patients. Treatment protocols for antiviral therapy are, however, similar to those used in immunocompetent individuals and although few long-term results are available, the efficacy of interferon and ribavirin therapy in hepatitis C virus/HIV infection and lamivudine in HIV/hepatitis B virus infection has been proven in the short-term. Perhaps the most important consideration is the timing of administering treatments to co-infected patients. For patients with well preserved CD4 counts and hepatitis C virus/HIV co-infection, the hepatitis infection should be treated as early as possible to avoid drug interactions of hepatitis C virus antivirals with antiretroviral therapy. Also, response to hepatitis C virus treatment appears better when treatment is administered in the context of preserved immune function. Conversely, in hepatitis B virus/HIV co-infection, hepatitis B virus antivirals are best administered with anti-retroviral therapy, thus preventing the selection of HIV viral species which may be resistant to the drugs used for hepatitis B virus. Improved graft and patient survival after liver transplant and with anticancer chemotherapy in hepatitis B virus infected patients has been proven using lamivudine prophylaxis. However, although therapy for hepatitis C virus recurrence after liver transplantation would seem rational, limited success with current treatment protocols has been achieved. SUMMARY: Although the prognosis of hepatitis B and C virus infections in the immune compromised may be inferior to that of immunocompetent individuals, such patients should have full evaluation of their viral hepatitis, and antiviral therapy should be considered.     

Management of the coinfected patient: human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C

Deaths from liver disease have increased in persons infected with human immunodeficiency virus (HIV) because of coinfection with chronic hepatitis B and C; consequently, all HIV-infected patients should be screened for hepatitis B and C, and all those susceptible should be vaccinated for hepatitis B. Hepatitis A vaccination is indicated for susceptible coinfected patients. It is also important to stress other means of preventing the transmission of hepatitis, such as safe sex and avoidance of blood exposures. Three oral agents, lamivudine, adefovir, and tenofovir, are active against hepatitis B infection. The need for highly active antiretroviral therapy and hepatitis B therapy should be addressed in a coordinated fashion, since two of these agents are active against both HIV and hepatitis B virus. Oral combination therapy for hepatitis B infection looks promising but needs further study. Combination therapy for chronic hepatitis C with pegylated interferon plus ribavirin is the most effective available therapy and the current standard of care. Prior to therapy, patients should be evaluated for contraindications to therapy. During treatment, they should be closely monitored for adverse events.     

R5 HIV productively infects Langerhans cells,and infection levels are regulated by compound CCR5 polymorphisms

Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Delta 32 revealed that LCs isolated from ORF Delta 32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Delta 32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORF Delta 32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORF Delta 32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection.     

Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains

T20 (generic name: Enfuvirtide, brand name: Fuzeon) is the only FDA-approved HIV fusion inhibitor that is being used for treatment of HIV/AIDS patients who have failed to respond to current antiretroviral drugs. However, it rapidly induces drug resistance in vitro and in vivo. On the basis of the structural and functional information of anti-HIV peptides from a previous study, we designed an HIV fusion inhibitor named CP32M, a 32-mer synthetic peptide that is highly effective in inhibiting infection by a wide range of primary HIV-1 isolates from multiple genotypes with R5- or dual-tropic (R5X4) phenotype, including a group O virus (BCF02) that is resistant to T20 and C34 (another anti-HIV peptide). Strikingly, CP32M is exceptionally potent (at low picomolar level) against infection by a panel of HIV-1 mutants highly resistant to T20 and C34. These findings suggest that CP32M can be further developed as an antiviral therapeutic against multidrug resistant HIV-1.     

Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies?

Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection.     

Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus

Nuclease-resistant phosphorothioate analogs of certain oligodeoxynucleotides have been tested in vitro as antiviral agents against human immunodeficiency virus (HIV) in human T cells. Phosphorothioate analogs complementary to HIV sequences, as well as noncomplementary analogs including homooligomers, exhibited potent antiviral activity. The antiviral activity was related to the base composition of the analogs, and longer phosphorothioates were more effective than shorter ones. A 28-mer phosphorothioate oligodeoxycytidine (S-dC28) at a concentration of 1 microM exhibited potent antiviral activity and inhibited de novo viral DNA synthesis as shown by Southern blot analysis. However, S-dC28 failed to inhibit gag expression in chronically infected T cells assessed by immunofluorescent assay at concentrations up to 25 microM. An N3-methylthymidine-containing phosphorothioate analog, which does not hybridize efficiently in vitro to complementary normal DNA, showed no antiviral activity. A 14-mer phosphorothioate oligodeoxycytidine (S-dC14) synergistically enhanced the antiviral activity of 2',3'-dideoxyadenosine, an anti-HIV nucleoside. Therefore, phosphorothioate analogs of oligodeoxynucleotides could represent a unique class of experimental therapeutic agents against the acquired immunodeficiency syndrome and related diseases. However, their mechanism of action is likely to be complex.     

Treatment of chronic hepatitis C: lessons from human immunodeficiency virus dynamics.

Treatment of chronic hepatitis C is a major problem. A sustained viral response to interferon alpha monotherapy occurs in <20% of patients. Using a combination therapy of interferon alpha and ribavirin. the sustained response rate in naive hepatitis C patients has increased to 31%-47%. The success of therapy for chronic hepatitis C depends on both virus- and host-related factors, such as age, histology, duration of hepatitis C virus (HCV) carriage and biochemical parameters. During the last 5 years, insight into the dynamics of human immunodeficency virus (HIV) has been obtained by analysing the changes in viral load after starting antiviral treatment. By using a mathematical model of HIV kinetics as an example, an exponentially rapid decline in serum HCV RNA level was seen after the first dose of interferon alpha, followed by a slower exponential decline: a so-called biphasic pattern. The estimated virion half-life varies between 2.7 and 16.8 h. The high virion turnover allows the generation of a heterogeneous quasi-species population of HCVs. It is therefore supposed that initial aggressive treatment can be helpful to prevent the development of mutations that make the virus more defensible for the interferon alpha treatment. Various trials are now being conducted based on this principle of high induction antiviral therapy.     

Malaria infection induces virus expression in human immunodeficiency virus transgenic mice by CD4 T cell-dependent immune activation

To test the capacity of malaria parasites to trigger virus expression in vivo, human immunodeficiency virus (HIV) transgenic mice were infected with Plasmodium chabaudi chabaudi clone AS. Splenocytes recovered during peak parasitemia showed a dramatic elevation in viral p24 production that returned to baseline by day 15 and failed to rebound at recrudescence or after reinfection. The major sources of virus expression were antigen-presenting cells (APCs) rather than T lymphocytes. Nevertheless, T cells from infected mice stimulated with plasmodial antigen triggered 5-10-fold increases in p24 production from dendritic cells in vitro, which suggests that viral induction stems from interaction of malaria-specific T lymphocytes with HIV-expressing APCs. Indeed, depletion of CD4 T cells resulted in a 70% reduction in the p24 response stimulated by malaria in vivo. These findings demonstrate the ability of Plasmodium species to immunologically activate latently integrated HIV in vivo but suggest that this process may be restricted to acute infection.