Christine Hogan

Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.

Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-1: a decade of experience.

Summary: Transmitted resistance to antiretroviral drugs in acute and early HIV-1 infection has been well documented, although overall trends vary depending on geography and cohort characteristics. To describe the changing pattern of transmitted drug-resistant HIV-1 in a well-defined cohort in New York City, a total of 361 patients with acute or recent HIV-1 infection were prospectively studied over a decade (1995-2004) with respect to HIV-1 genotypes and longitudinal T-cell subsets and HIV-1 RNA levels. The prevalence of overall transmitted resistance changed from 13.2% to 24.1% (P = 0.11) during the periods 1995 to 1998 and 2003 to 2004. Nonnucleoside reverse transcriptase inhibitor resistance prevalence increased significantly from 2.6% to 13.4% (P = 0.007) during the same periods, whereas prevalence of multidrug-resistant virus shifted from 2.6% to 9.8% (P = 0.07) but did not achieve statistical significance. A comparable immunologic and virologic response of appropriately treated individuals was observed regardless of viral drug susceptibility status, suggesting that initial combination therapy guided by baseline resistance testing in the case of acute and early infection may result in a favorable treatment response even in the case of a drug-resistant virus. These data have important implications for selection of empiric first-line regimens for treatment of acutely infected antiretroviral-naive individuals and reinforce the need for baseline resistance testing in acute and early HIV-1 infection.

Host Determinants in HIV Infection and Disease: Part 2: Genetic Factors and Implications for Antiretroviral Therapeutics*

A complex interplay of host and viral factors, many of which are only beginning to be understood, determines the course of HIV infection. The existence of long-term nonprogressors and exposed yet uninfected persons suggests that natural and acquired immunity to HIV exists and is a major determinant of clinical outcome. This article, the second of two reviewing the role of host factors in HIV infection, discusses the role of genetic host factorsnamely, inheritance of mutant chemokine receptors or ligands as well as HLA typein susceptibility to infection with HIV and subsequent clinical course. The effects of soluble inhibitory factors, the cytokine milieu, and concomitant infections are also described (Table 1, Figure 1). Figure 1. Schematic overview of host responses at the cellular, local, and systemic levels. CTLs R5 X4 MIP SDF IFN IL TNF Table 1. Host Factors in HIV Infection Methods Studies for inclusion were identified by a systematic search of PubMed for English-language literature published from 1988 through June 2000. Abstracts of presentations at major meetings convened in 2000 were also included if appropriate. The text and references in this article reflect a synthesis of the available information and an attempt to place this information in the context of the current state of the art. The funding sources had no direct role in the preparation of this paper or in the decision to submit the paper for publication. Chemokines, Cytokines, and Other Soluble Factors Chemokines A breakthrough in our understanding of HIV pathogenesis, and thus in our understanding of host factors that can affect disease progression and susceptibility to infection, was the identification in 1996 of chemokine receptors as necessary co-receptors for HIV entry into CD4+ cells. Chemokines are chemoattractant substances secreted at sites of infection or injury (64). It had been known since the mid-1980s that presence of CD4 on a cell surface was necessary but not sufficient for entry of HIV into the cell. In addition, it was known that CD8 cells secrete substances that interfere with the ability of HIV to infect cells. In 1995, Cocchi and colleagues (1) identified these substances as RANTES (regulated on activation, normal T expressed and secreted); macrophage inflammatory protein-1 (MIP-1); and MIP-1. It was hypothesized that these substances bind to a receptor that the virus requires for cell entry. In 1996, Feng and associates (2) isolated CXCR4 (originally referred to as fusin), a chemokine receptor located on T cells that T-celltropic (T-tropic) HIV uses as a co-receptor along with CD4. However, it was known that RANTES, MIP-1, and MIP-1 suppressed macrophage-tropic (M-tropic) but not T-tropic virus. In the same year, several groups published results showing that the receptor for RANTES, MIP-1, and MIP-1 was a chemokine receptor called CCR5 (originally referred to as CKR-5) that is present on macrophages, monocytes, and some T cells (3-8). Human immunodeficiency virus uses these chemokine receptors as co-receptors for entry. The interaction between the virus envelope protein gp120 and CD4 induces a conformational change that allows interaction between the virus and the chemokine receptor and ultimate fusion of the virus and host cell membrane (65-68). Thus, the currently held model is that M-tropic HIV strains (termed R5 viruses) infect macrophages, monocytes, and T cells by using the hosts expression of CD4 and CCR5 as co-receptors. T-tropic HIV strains (termed X4 viruses) infect T cells by using CD4 and CXCR4 as co-receptors (69) (Figure 2). However, the chemokine system is complex and often redundant, and the above model does not always apply. For example, some M-tropic strains of HIV can use other co-receptors, such as CCR2 or CCR3, instead of CCR5 for entry into macrophages. In addition, syncytium-inducing variants with dual tropism that can use CCR5 or CXCR4 as co-receptors have been isolated (6, 7, 70). Figure 2. Interaction of HIV with its coreceptors. M-tropic R5 RANTES MIP T-tropic X4 SDF-1 The hosts natural ligands for these co-receptors are relevant because they may interfere with HIV entry into target cells (Table 2). CCR5 binds RANTES, MIP-1, and MIP-1, which are members of the -chemokine family and are often referred to as CCR5-using chemokines. CXCR4 binds a member of the -chemokine family, stromal cellderived factor-1 (SDF-1). CCR2 binds monocyte chemotactic protein-1 (MCP-1) through MCP-5. CCR3 binds MCP-3 and MCP-4 and eotaxin 1 and 2 (64). For further information on other chemokine receptors that serve as co-receptors for HIV and simian immunodeficiency virus (SIV), see reference 92. Table 2. Selected Chemokine Receptors and Ligands The ligands for the chemokine receptors can block viral entry by interfering with viral binding to the receptor or by downregulating the receptor (93). The CCR5-using chemokinesRANTES, MIP-1, and MIP-1can block M-tropic strains of HIV, whereas SDF-1 blocks T-tropic strains. CD4 T cells from exposed yet uninfected persons have been shown to produce increased levels of RANTES, MIP-1, and MIP-1 and to suppress replication of M-tropic strains of HIV-1 (94, 95). High levels of CCR5-using chemokines have been associated with slower disease progression (96). However, other studies have found no quantitative difference in production of RANTES, MIP-1, or MIP-1 by peripheral blood mononuclear cells of 16 discordant heterosexual couples (97) or between long-term nonprogressors and progressors (98). Some in vitro studies have even suggested that RANTES, MIP-1, and MIP-1 may upregulate replication of HIV in macrophages and monocytes by recruiting activated target cells (99-101). Furthermore, in vivo levels of RANTES in HIV-infected persons have been shown not to be correlated with HIV-1 viral load (102). Further research is needed to clarify the true clinical relevance and regulatory roles of these and other chemokines in HIV infection (103, 104). The finding that chemokine receptors are used by HIV as co-receptors for cellular entry led to the discovery of genetic host factors that can affect susceptibility to infection with HIV or the rate of progression to disease once infection is established. The best characterized of these genetic traits is the CCR5- 32 mutation, which was identified in 1996 (9, 10). The mutation is a 32base pair deletion that results in a shortened protein. In the United States, the frequency of the allele is 11% in white persons but only 1.7% in black persons. Persons who are homozygous for the deletion have decreased susceptibility to infection with HIV, although they can still be infected with T-tropic strains of the virus, which use the CXCR4 co-receptor for cell entry (9, 11, 12). Dean and colleagues (9) studied a cohort of persons with hemophilia, intravenous drug users, and men who have sex with men. Seventeen of 612 uninfected persons (compared with 0 of 1343 infected persons) were homozygous for the CCR5-32 mutation. In addition, the Chicago arm of the Multicenter AIDS Cohort Study of men who have sex with men revealed a 3.6% prevalence of homozygosity among at-risk but uninfected persons compared with a 1.4% prevalence in blood samples from random white men and 0% prevalence among HIV-infected persons (11). Reports of HIV-infected persons homozygous for the CCR5-32 mutation exist but are rare (105-108). One study of such a person demonstrated that the virus isolated from this person was homogeneous, T-tropic, and syncytium-inducing and exclusively used CXCR4 for entry (13). With few exceptions (14, 15), most studies have found that persons heterozygous for the CCR5- 32 mutation are not less susceptible to HIV infection (9, 11, 12). Data do suggest, however, that heterozygotes for the CCR5- 32 mutation have delayed progression to AIDS or death (11, 12, 16-20). In the study by Dean and colleagues (9), the frequency of heterozygosity was significantly greater in long-term nonprogressors than in progressors and rapid progressors. Liu and coworkers (10) found that peripheral blood mononuclear cells of parents of uninfected homozygous persons replicated virus less efficiently. Presumably, heterozygosity limits the number of co-receptors available for HIV binding. Indeed, CCR5 density on the surface of the CD4+ T cell has been correlated with viral load in persons with untreated HIV-1 infection (21). Studies incorporating viral phenotype have suggested that the protective effect of CCR5- 32 heterozygosity against disease progression is lost when the infecting virus is syncytium-inducing or T-tropic (109, 110), although this has not been confirmed in other studies (18). This discrepancy may be due to dual tropism of syncytium-inducing viruses. Several other mutations in the coding region of the CCR5 gene have been identified (111). A point mutation in CCR5a TA substitution at position m303encodes a truncated protein and, when found in the compound heterozygous state with 32, produces a phenotype of resistance to HIV-1 primary isolates in vitro (112, 113). Another genetic mutation that affects disease progression is the CCR2-V64I mutation, which results in normal levels of expression of the CCR2 receptor. This mutation has not been shown to affect susceptibility to infection, but HIV-infected persons heterozygous or homozygous for this mutation appear to progress to AIDS or death more slowly (16, 17, 19, 22-26); some studies, however, have not confirmed this effect on progression to disease (20, 27-29). Unlike the CCR5 mutation, which is found primarily in white persons, the frequency of the CCR2-V64I allele is 10% to 25% in both black and white persons and in all other ethnic groups studied. Studies of infected commercial sex workers in Nairobi, Kenya, suggested that the presence of the mutation helped to explain slow progression in 21% to 46% of slow progressors (22). It is unclear how heterozygosity for a mutant form of a chemokine receptor that most strains of

Host Determinants in HIV Infection and Disease: Part 1: Cellular and Humoral Immune Responses*

The course of HIV infection varies widely among individuals. The median time from infection to development of AIDS is 8 to 10 years, but a small proportion of patients, probably no more than 5% to 10%, have been characterized as long-term nonprogressors. These persons have been identified among HIV-infected persons whose risk factors include sexual exposure, intravenous drug use, and transfusions (1-8). Strictly defined, long-term nonprogressors are those who, in the absence of treatment, remain asymptomatic and have normal CD4 cell counts and low or undetectable viral loads despite prolonged periods of infection with HIV. Of note, a substantial proportion of such patients described in the literature have subsequently demonstrated progressive immunodeficiency. In this review, the term long-term nonprogressors is used to mean true long-term nonprogressors and slow progressors. In contrast, perhaps 10% of all HIV-infected persons are rapid progressors who develop AIDS within 5 years of infection with HIV (6, 9). Identification of these patients has led to comparison of persons with different rates of disease progression in order to elucidate the factors that determine an individuals risk for progression. The interaction of numerous viral and host factors, such as viral virulence, host genetics, host immune response, and cytokine milieu is believed to determine the course of disease. In addition, several groups that are at risk for HIV infection but have not become infected have been reported. These exposed yet uninfected persons have been identified among discordant couples who have unprotected sex (10-16), commercial sex workers (17-19), intravenous drug users (20), health care workers who sustain needlestick injuries with HIV-infected blood (13, 21, 22), and infants of seropositive mothers (23, 24). Thus, the interaction of complex host and viral factors may determine not only progression to disease but also the risk for initial HIV acquisition. The existence of long-term nonprogressors and exposed yet uninfected persons suggests that natural and acquired immunity to HIV exist and are major determinants of clinical outcome. Immunologic and genetic studies of long-term nonprogressors and exposed yet uninfected persons, as well as data from studies of primary HIV infection, have helped to elucidate the mechanisms by which some persons are protected from HIV acquisition or demonstrate slow rates of disease progression (Table 1, Figure 1). Figure 1. Schematic overview of host responses at the cellular, local, and systemic levels. CTLs R5 X4 RANTES MIP SDF IFN IL TNF Table 1. Host Factors in HIV Infection This review, the first of two parts, describes what is currently known about host factors in HIV acquisition and progression and discusses how this knowledge can be used to prevent and treat HIV infection. Part 1 discusses the growing evidence that suggests a crucial role of cytotoxic T cells and T-helper cells in controlling viremia, slowing disease progression, and perhaps preventing establishment of infection. The role of humoral and mucosal immunity and other local factors is also discussed. Part 2 will describe the role of genetic host factors, such as mutant chemokine receptors and HLA type, as well as soluble inhibitory factors, the cytokine milieu, and concomitant infection. Methods Studies were identified by a systematic search of PubMed for English-language publications from 1988 through June 2000 and, where appropriate, abstract presentations from major meetings convened in 2000. The text and references in this article reflect a synthesis of the available information and an attempt to place this information in the context of the current state of the art. The funding sources had no direct role in the preparation of this paper or in the decision to submit the paper for publication. Current Concepts in Viral Pathogenesis In the context of a discussion of host determinants in HIV infection and disease, it is important to recognize characteristics of the pathogen that interact with these host factors and codetermine outcome (Table 2). Table 2. Selected Viral Factors VirusHost Interactions The pathogenesis of HIV infection involves infection of and replication within CD4-bearing host cells, including CD4+ T-cell lymphocytes and, to a lesser degree, macrophages and dendritic cells. Ongoing replication within and destruction of CD4+ T cells, which are key effector cells in the hosts immune response, eventually lead to profound immunosuppression clinically recognized as AIDS. To enter cells, HIV requires a co-receptor in addition to CD4. Understanding of these co-receptorsprimarily CCR5 and CXCR4and their natural ligands has provided new insights into hostpathogen interactions. It was previously believed that the period between infection and progression to AIDS, known as the clinically latent period, reflected underlying viral latency. However, progressive HIV activity in lymphoid tissue had been described (101), and Ho (102) and Wei (103) and their colleagues showed that viral replication persists throughout infection at a staggering rate; at least 1010 virions are produced and cleared each day in an infected person. The half-life of virions in circulation is less than 6 hours and may be less than 30 minutes, and the half-life of actively infected CD4+ T cells is 1.5 days (104-108). In addition, the viral replication process, mediated in part by the reverse transcriptase of HIV, is prone to error and produces new mutations each day (109). The diversity within the viral genome therefore increases throughout infection, leading to potential escape from the hosts immune response and resistance to chemotherapeutic agents. During primary infection with HIV, high levels of viremia develop within days to weeks (110-112). This event is often accompanied by an acute retroviral syndrome, characterized by such nonspecific symptoms as fever, fatigue, pharyngitis, rash, lymphadenopathy, and, frequently, aseptic meningitis (113-115). Vigorous systemic immune activation provides a large supply of activated CD4+ lymphocytes to support HIV replication, although recent animal and human data suggest that activation of T cells is not an absolute requirement for infection (116). Viremia reaches a peak, and the CD4 cell count acutely decreases. Within weeks to months (120 days in one prospective cohort study [117]), as the host mounts a vigorous immune response that partially controls viral replication, a hypothesized viral set-point is reached, reflecting a tenuous balance between production and destruction of virions, and CD4 cell counts return to near normal. This viral set-point is not absolute and has been shown to be inversely correlated with time to disease progression (117-120). The host enters a largely asymptomatic phase during which viremia persists, and billions of virions and CD4 cells are produced and destroyed daily. Eventually, progression to disease occurs, characterized by steadily increasing viremia, decreasing CD4 cell counts, and, finally, profound immunosuppression. Viral Tropism Two major variants of HIV-1 with respect to tropism have been identified. Soon after seroconversion, HIV isolates tend to be of a nonsyncytium-inducing phenotype. These nonsyncytium-inducing variants are also referred to as macrophage-tropic or M-tropic because in vitro, they infect monocyte-derived macrophages but not established CD4+ T-cell lines. Another variant of HIV-1 with a syncytium-inducing phenotype preferentially infects T-cell lines and is thus referred to as T-tropic. Of note, M-tropic and T-tropic variants infect primary CD4+ T lymphocytes. The distinction between phenotypes is based on growth of T-tropic but not M-tropic isolates in T-lymphoblastoid cell lines. Some dual-tropic isolates can grow in T-lymphoblastoid cell lines and macrophages (121). Early HIV infection is characterized by M-tropic strains, whereas the syncytium-inducing variants tend to emerge during a later stage of HIV infection. As the virus mutates and the phenotype shifts, T-tropic strains eventually emerge; these strains have been linked to increased cytopathogenicity, resulting in more rapid T-cell depletion (82-86, 113, 122-124). This transition between phenotypes, which has been linked to evolution in co-receptor use (87, 88, 125), is not necessary for disease progression, and in some cases it never occurs. Viral Escape In addition to cell tropism, viral escape from the immune response has been implicated in pathogenesis (126, 127). The ability of HIV to persistently replicate despite a vigorous HIV-specific cell-mediated and humoral immune response suggests that the virus may use several mechanisms for evading the immune response. These include antigenic variation, such that unrecognized epitopes are presented to T cells and activation of the effector cells does not occur (72-74); downregulation of MHC molecules on the surface of HIV-infected cells (75); and disappearance of initially expanded HIV-specific CD8 cells through clonal exhaustion (76, 77). In addition, the virus may persist in immune-privileged sites, such as the central nervous system, eye, and testis, where exposure to effector immune cells is avoided. Lymph-node follicular dendritic cells can trap HIV, where it can remain viable for an extended period (128-130). Infection of resting memory T cells by HIV results in a latent reservoir of HIV, because these resting cells do not express viral products and thus are not recognized by effector immune cells (131, 132). Viral Attenuation Several reports have strongly suggested that attenuated HIV can slow the rate of disease progression (78, 133, 134). Slowly progressive infection has been reported in persons harboring a strain of HIV-1 with a deletion in the nef gene (79, 80). The Sydney Blood Bank Cohort, for example, is a group of eight HIV-infected persons who were infected from a common donor whose virus had a defective nef gene.

Determining the Relative Efficacy of Highly Active Antiretroviral Therapy

Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%. However, it is important to emphasize that further study is warranted to explore whether these early measurements of relative efficacy provide long-term virologic and clinical benefits. Nevertheless, we believe that optimal treatment regimens for HIV-1 have yet to be identified and that continued research to achieve this goal is warranted.

Neutralization Profiles of Newly Transmitted Human Immunodeficiency Virus Type 1 by Monoclonal Antibodies 2G12, 2F5, and 4E10

ABSTRACT As the AIDS epidemic continues unabated, the development of a human immunodeficiency virus (HIV) vaccine is critical. Ideally, an effective vaccine should elicit cell-mediated and neutralizing humoral immune responses. We have determined the in vitro susceptibility profile of sexually transmitted viruses from 91 patients with acute and early HIV-1 infection to three monoclonal antibodies, 2G12, 2F5, and 4E10. Using a recombinant virus assay to measure neutralization, we found all transmitted viruses were neutralized by 4E10, 80% were neutralized by 2F5, and only 37% were neutralized by 2G12. We propose that the induction of 4E10-like antibodies should be a priority in designing immunogens to prevent HIV-1 infection.

The Setpoint Study (ACTG A5217): Effect of Immediate Versus Deferred Antiretroviral Therapy on Virologic Set Point in Recently HIV-1–Infected Individuals

BACKGROUND The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. METHODS A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). RESULTS At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. CONCLUSIONS Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. CLINICAL TRIALS REGISTRATION NCT00090779.

Viral Blip Dynamics during Highly Active Antiretroviral Therapy

ABSTRACT Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e., plasma VL measurements of >50 copies/ml, in 123 HAART-treated patients monitored for a mean of 2.6 years (range, 5 months to 5.3 years). The mean (± the standard deviation) blip frequency was 0.09 ± 0.11/sample, with about one-third of patients showing no viral blips. The mean viral blip amplitude was 158 ± 132 human immunodeficiency virus type 1 (HIV-1) RNA copies/ml. Analysis of the blip frequency and amplitude distributions suggest that two blips less than 22 days apart have a significant chance of being part of the same episode of viremia. The data are consistent with a hypothetical model in which each episode of viremia consists of a phase of VL rise, followed by two-phase exponential decay. Thus, the term “viral blip” may be a misnomer, since viral replication appears to be occurring over an extended period. Neither the frequency nor the amplitude of viral blips increases with longer periods of observation, but the frequency is inversely correlated with the CD4+-T-cell count at the start of therapy, suggesting that host-specific factors but not treatment fatigue are determinants of blip frequency.

Dynamics of Intermittent Viremia during Highly Active Antiretroviral Therapy in Patients Who Initiate Therapy during Chronic versus Acute and Early Human Immunodeficiency Virus Type 1 Infection

ABSTRACT The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofold higher in CHI patients (0.122 ± 0.12/viral load [VL] sample, mean ± standard deviation) than in PHI patients (0.066 ± 0.09/VL sample). However, in both groups, viral blip frequency did not increase with longer periods of observation. Also, no difference in viral blip frequency was observed between treatment subgroups, and the occurrence of a blip was not associated with a recent change in CD4+ T-cell count. Finally, in PHI patients the VL set point was a significant predictor of blip frequency during treatment.

The Virologic and Immunologic Effects of Cyclosporine as an Adjunct to Antiretroviral Therapy in Patients Treated during Acute and Early HIV-1 Infection

Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4(+) T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit.