VIRAL AND IMMUNOPATHOGENESIS OF VERTICAL HIV-1 INFECTION

HIV/ AIDS IN INFANTS, CHILDREN, AND ADOLESCENTS

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VIRAL AND IMMUNOPATHOGENESIS OF VERTICAL HIV-1 INFECTION Katherine Luzuriaga, MD, and John L. Sullivan, MD

The transmission of HIV-1 from infected women to their infants (i.e., vertical transmission) is the primary mode of pediatric HIV-1 infection. The vertical transmission of HIV-1 may occur during gestation (in utero), delivery (intrapartum), or breast-feeding (postpartum). The clinical course of vertical HIV-1 infection is highly variable from individual to individual, but before the widespread use of potent antiretroviral therapies, two general patterns of survival were described in vertically infected children?, 5, Approximately 10% to 20% of infants experience rapid progression of disease and die of AIDSrelated complications by 4 years of age. The mean survival time of the remaining 80% to 90% of infected children is approximately 9 to 10 years. Although the survival rate among HIV-1 infected children resembles that of adults, HIV-1 related symptoms or CD4 T-cell depletion develops in most untreated vertically infected children within the first few years of life. In a prospectively evaluated cohort of 200 vertically infected infants,2*the median age of onset of any HIV-1-related sign or symptom was 5.2 months; the probability of remaining asymptomatic was 19.0%(95% confidence interval, 14-25) at 1 year and 6.1% (95% confidence interval, 2.6-11.7) at 5 years. In another large, prospective cohort study,63 AIDS-defining conditions developed in approximately 23% and 40% of vertically infected infants by 1 and 4 years of age, respectively. Multiple aspects of the virus-host dynamic have been examined as potential explanations for the observed interpatient variability in disease progression following vertical HIV-1 infection.

From the Department of Pediatrics, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts

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VIRAL DETERMINANTS OF THE CLINICAL SEQUELAE OF VERTICAL HIV-1 INFECTION Timing of Vertical Transmission

The use of the polymerase chain reaction to detect HIV-1 DNA in peripheral blood lymphocytes has markedly improved the understanding of the timing of infection. The detection of HIV-1 DNA using the polymerase chain reaction in peripheral blood lymphocytes taken at birth suggests in utero infection'" 51, "; this pattern of infection is observed in up to 30% of infants. In most infants worldwide, HIV-1 DNA is not detected in peripheral blood lymphocytes at birth but becomes detectable after several days of life, suggesting that most vertical HIV-1 infections seem to occur at the time of delivery. In developing countries, a significant proportion (5 13%) of infants seem to acquire HIV-1 infection postpartum through breast-feeding. Several studies have demonstrated an increased risk for vertical HIV-1 transmission, with increasing time intervals between the rupture of chorionic membranes and delivery of infants,&,90 supporting the conclusion that most infants worldwide acquire HIV-1 infection at delivery. Results from perinatal intervention trials also provide support for this conclusion. Marked reductions in vertical HIV-1 transmission rates have been observed when antiretroviral regimens were administered around the time of delivery?' When the administration of antiretroviral therapy is combined with cesarean section performed before the onset of labor, vertical HIV-1 transmission occurs only rarely." 55 Characteristics of Transmitted Viruses

The application of polymerase chain reaction to detect, quantify, and characterize viruses in peripheral blood and tissues has markedly improved the understanding of events in early infection. Comparisons of maternal viruses to infant viruses obtained in early vertical HIV-1 infection have revealed genotypic and phenotypic differences suggestive of the selective transmission or post-transmission amplification of a single viral strain. The ability of distinct viral strains to infect different cells of hematopoietic lineage has been described and is referred to as cellular tropism. Viruses obtained from infants in early infection display limited cell tropism in vitro. All HIV-1 strains infect primary CD4 T lymphocytes (i.e., CD4 T lymphocytes directly isolated from the peripheral blood) and replicate in activated CD4 T lymphocytes. Most viruses that are directly isolated from HIV-l-infected individuals also infect and replicate well in macrophages (M-tropic); others (particularly those that undergo extensive passage in lymphoid cells in vitro18,lol) also infect and replicate in immortalized T-cell lines (T-tropic). Most HIV-1 strains isolated from individuals during primary infection (including early vertical infection) are M-tropic, regardless of the route of exposure (i.e., mucosal versus intravenous), even when the virus donor may harbor M-tropic and T-tropic viruses. The diversity of HIV-1 envelope third variable region gene sequences of viruses obtained shortly following vertical HIV-1 infection is limited compared with the maternal sequences.8z,98 Although data from several laboratories suggested that sequences within the third variable region (V3) of the HIV-1 envelope gp120 were important determinants of cellular tropism, the molecular basis for this observation was not well understood until cellular HIV-1 coreceptors were identified.

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The CD4 molecule is the primary cellular receptor for HIV-1. Cells that express CD4 on their cell surfaces (i.e., CD4 T cells and cells of monocyte or macrophage lineage) are major targets for HIV-1 infection." Although the expression of CD4 on the cell surface was usually necessary for HIV-1 infection, it was not always sufficient. The transfection of the human CD4 molecule into nonsusceptible human cells resulted in susceptibility to infection. By contrast, murine cells were not rendered susceptible to infection by the transfection of human CD4" except when previously fused with human cells." This suggested the expression of one or more second receptors on human cells that facilitated virion-cell membrane fusion and postentry events in viral replication. Demonstration that the P-chemokines, RANTES, MIP-la, and MIP-1P, suppress the replication of primary clinical isolates of HIV-1 in vitro" led to the identification of chemokine receptors as HIV-1 coreceptors. Cellular chemokine receptors are seven-transntembrane, G-protein-coupled receptors73that transduce chemokine binding into intracellular signals. All HIV-1 strains use either the CCR5 or CXCR4 (also known as LESTR or fusin) coreceptors; some use both. M-tropic strains seem to preferentially use the CCR5 coreceptor, whereas Ttropic strains preferentially use CXCR4, although several dual-tropic strains have been described. Envelope V3 region sequences seem to influence coreceptor usage. Primary HIV-1 isolates are also able to use other coreceptors in vitroZ0; the extent to which other coreceptors are used by M-tropic and T-tropic viruses and the potential contribution of other coreceptors to the establishment of infection are currently under evaluation. Data supporting the importance of the CCR5 coreceptor in early HIV-1 infection comes from the identification of a 32-base pair deletion in CCR5 in noninfected adult individuals at high risk for infection through sexual or parental exposure.48,68 Lymphocytes from these individuals do not express CCR5 on their cell surfaces and are relatively resistant to infection with primary HIV-1 isolates in vitro. Of interest is that heterozygous and homozygous individuals seem to be phenotypically but at least four HIV-1 infected individuals homozygous for the 32-base pair deletion in the CCR5 gene have been described: suggesting that, under some circumstances, other coreceptors might be used in the establishment of infection. Although heterozygosity for the CCR5 deletion mutant does not seem to protect from the acquisition of infection, pediatric6O and adultz studies indicate that it might protect against disease progression. The assessment of the potential role of cellular coreceptors in the pathogenesis of vertical HIV-1 is complicated by the variability in the cell-surface expression of the coreceptors. Some studies have demonstrated that the cell-surface expression of CCR5 can vary markedly from individual to individual, even among individuals homozygous for the wild-type gene.* The percentage of cells expressing CCR5 and the lymphocyte cell-surface receptor density are reduced in heterozygotes compared with homozygous wild-type individuals. The cell-surface expression of CCR5 and CXCR4 also varies among cell types or subpopulations. For example, investigators have reported that CXCR4 is predominantly expressed on naive, quiescent CD4 T cells, whereas CCR5 is expressed predominantly on activated or memory CD4 T cells.1oFinally, the cell surface expression of these coreceptors may depend on the cytokine milieu; for example, the addition of interleukin 2 to T-cell cultures can up-regulate CCR5 and CXCR4 expression." Additional work is necessary to investigate the potential ramifications of these observations for the pathogenesis of HIV-1 infection in vivo.

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Early Viremia and Kinetics of Viral Replication

In the weeks following adult or pediatric infection, rapid increases in plasma HIV-1 load are observed; in these first few weeks, plasma HIV-1 RNA copy numbers of lo5 to lo7 per milliliter of plasma are common.1,ffi* 84 In patients with adult primary infection, peak plasma HIV-1 RNA levels rapidly diminish by 100-fold to 1000-fold within 1 or 2 months following the onset of ~ymptorns.5~ This decrease is observed even in the absence of antiretroviral therapy and is thought to be caused by containment by host immune responsesll, 12, 42 or the exhaustion of permissive host cells.7oBy 6 to 12 months following primary infection, a steady-state plasma HIV-1 RNA level is reached and is independently predictive of the rate of subsequent disease progressi~n.~~, 59 In infants, plasma HIV-1.RNA levels remain high over the first 1 or 2 years mean plasma HIV-1 RNA levels do not decrease to less than lo5 of life’, 65, @; copies/mL plasma through at least the third year of life. A continued reduction in plasma HIV-1 RNA (mean, -0.2 to -0.3 log decline per year) has been 61 observed in vertically infected children through 5 or 6 years of age.57, Although differences in peripheral blood viral load during early infancy did not seem to affect disease progression in one study,@others have reported that higher early peripheral blood viral load increases the risk for rapid progression.’, 26 After 1 or 2 years of age, although some overlap is observed in plasma HIV-1 RNA levels of rapid and slow progressors, higher plasma HIV-1 RNA levels are associated with an increased risk for progression to AIDS or death.61Reductions in plasma HIV-1 RNA following the initiation of antiretrovi8o ral therapy have been associated with clinical benefit in adults and children.66, Multiple factors may contribute to the prolonged elevation of plasma HIV1 RNA levels in early vertical infection. These include the kinetics of viral replication, size of the pool of host cells that are permissive to viral replication, and deficient virus-specific immune responses. Potent combination antiretroviral therapy regimens have been used to estimate the kinetics of HIV-1 replication in infected infants and children.53Following the initiation of therapy, the clearance of HIV-1 virions in plasma was biphasic. Most (> 90%) virus in plasma was cleared during an initial rapid, exponential decrease. A slower, exponential second-phase decrease was then observed. This pattern of virion clearance is similar to those previously described in cohorts of adults experiencing primary infection47and in adults with established disease.69The consistency is striking given the diversity in age, viral load, disease stage, and CD4 counts of the patient populations studied, in addition to the various treatment regimens used. H032and Perelson et aP9 suggest that the observed biphasic pattern of viral clearance likely represents two distinct cellular sources for plasma virions: (1) short-lived, productively infected cells (i.e., CD4 T cells; first phase) and (2) long-lived cells with stably integrated HIV-1 provirus (i.e., tissue macrophages, dendritic cells, or latently infected CD4 T cells undergoing activation; second phase). Alternatively, the biphasic decay following the initiation of therapy could represent an exponential decay of viral production by a single cellular source, with a decreasing exponent over time caused by a reduction in the number of virus-producing cells or the ability of the cells to produce virus ( e g , an increased number of cells moving from the activated state to a resting state). Viral decay rates were used to calculate half-lives for viral turnover. During the first phase of viral decay (representing > 90% of plasma virus), half of the plasma virus turned over approximately every 30 hours on average in the

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younger group and approximately every 14 hours on average in the older group. These estimates are similar to those calculated for adults. Although viral replication dynamics in children may be similar to those in adults, a large and renewable pool of permissive host cells may contribute to persistently high plasma HIV-1RNA levels in infancy and early childhood. CD4 T cells and thymocytes might be particularly important substrates in young i1dants.9~Relative lymphocytosis and an increased 0 4 T-cell pool size are observed in infancy and through early childhood, but relatively few circulating CD4 T cells in early childhood are of the memory phenotype. The memory subset of T cells seems to express higher levels of CCR5l0and seems to be more permissive for HIV-1 repli~ation'~,86 than naive T cells. Moreover, the decrease in plasma HIV-1 RNA levels (10-fold to 100-fold) far exceeds an age-related three-fold reduction in CD4 T cells observed over the same time period57;the production of multiple virionsby an infected cell might explain this observation. Thymic mass relative to body size is extremely high, and thymopoiesis is particularly active in fetuses and young infants. This expanded thymocyte pool might also contribute to prolonged elevation of plasma HIV-1 RNA levels in infants. Several groups have demonstrated that thymocytes may be infected with HIV-l?5,89 These studies have primarily used T-tropic, laboratory-adapted viruses, and a higher frequency and cell-surface density of CXCR4 expression have been described on immature thymocytes than in more mature cells." The frequency, cell-surface density of CCR5, expression of other coreceptors, and corresponding infectability of thymocytes by primary viruses require additional study. Host Factors Affecting the Rate of Disease Progression

In the macaque model of SIV infection, divergent rates of disease progression following the administration of a molecular viral clone suggest the importance of host factors in the pathogenesis of lentiviral disease.40Age at infection seems to be a particularly important determinant of o~tcome,~, especially when the viral inoculum is high. Young hosts' immune systems might provide a larger pool of cells permissive for HIV-1 infection. Infection at a time of reduced ability to generate effective virus-specific immune responses might also account for the apparent diminished control of viral replication in infancy and early childhood. Support for this hypothesis is provided by studies that suggest that host immune system selective forces seem to be major determinants of diversification of the viral q~asispecies,2~,~~ together with other studies that have documented limited viral diversification over the first 6 months of In addition, several immune effector functions may require more time to develop in infancy. Cellular Immunity

Cell-mediated immunity is especially important for the control of intracellular pathogens. The increased severity of many viral infections in neonates and infants suggests a reduced capacity to generate effective cell-mediated immune responses.15 Several studies have documented adult levels of antigen-presenting cells (i.e., macrophages and dendritic cells) and effector cells (natural killer [NK] cells and CD4 and CD8 T cells) in neonates. By contrast, some effector responses, such as the production of certain cytokines (i.e., interferon y and interleukin 495),

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proliferation,2I and cytotoxicity seem to be diminished in early infancy (see references 94 and 87 for reviews). Recent human3 and murineZ7,75, 81 studies suggest that the efficiency of antigen presentation by neonatal dendritic cells is diminished, especially in generating effector responses from naive T cells (which constitute most circulating T cells in fetuses and newborns), but these same murine studies suggest that alterations in the nature, dose, and route of antigen administration may improve the capability of neonatal animals to generate cellmediated immune responses. These data, together with the data outlined later, have important implications for the development of a neonatal vaccine to prevent vertical HIV-1 infection. Natural Killer Cells I

Natural killer cells are lymphocytes that are important in the early, nonspecific recognition of altered self. In some murine viral infections, NK cells have a major role in the control of early viral replication before the development of an active virus-specific cytotoxic T lymphocyte (CTL) response." Viruses that stimulate the down-regulation of major histocompatibility complex class I molecule expression on the surface of virus-infected cells seem to be especially potent inducers of NK-cell responses. In humans, NK cells have been shown to be important in the early phase of primary infections with herpes~iruses,~ although herpsevirus-specific, ceIl-mediated immunity (i.e., CTL response) seems necessary for the ultimate control of viral replication. Natural killer cells are detected in fetuses by 6 weeks of gestation; by midgestation, their numbers equal the numbers found in adults. The ability of neonatal NK cells to directly kill HIV-1 infected cells seems to be equivalent to that of NK cells taken from but antibody-dependent, NK cell-mediated cytotoxicity (ADCC) is diminished in neonates and does not approach adult levels until approximately 1 month of age (A. Alimenti, MD, and K. Luzuriaga, MD, unpublished observations, 1991). HIV-1-Specific Cytotoxic T Lymphocyte Responses in Vertically Infected Infants

Virus-specific CTLs are important for the clearance of acute viral infection and suppression of viral replication in chronic infections, although they likely act in synergy with other virus-specific or nonspecific immune responses (reviewed in reference 64). The extent to which CTLs are important in a viral infection may depend on key viral characteristics, such as cell tropism and viral replication rate. In HIV-1 infected adults, HIV-1-specific CTLs have been detected soon after infection", and seem to persist throughout the course of infection. In contrast to other viral infections, HIV-1 specific CTLs have been demonstrated in the absence of virus-specific in vitro stimulation ("activated CIYe). Also, an individual may generate CD8 + HIV-1-specific CTLs directed against multiple structural (env, gag; reviewed in references 39 and 79) or nonstructural (reverse transcriptase, nef" ") epitopes. Several lines of evidence suggest that a robust HIV-1-specific CTL response protects against disease progression. The temporal association of the detection of HIV-1-specific CTLs with a reduction of blood viral load and diversification of the quasispecies in adult primary viremia suggest a protective role. The

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association of high HIV-1-specific CTL precursor fkquencies with preservation of CD4 counts31also supports a protective role. Brodie et all3have demonstrated that adoptively transferred, autologous, HIV-l-specific CTLs home to sites of viral replication and seem to exert local antiviral effects. In many HIV-1-infected individuals, however, high-level viral replication often continues in the presence of an apparently vigorous HIV-l-specific CTL response. Widespread dissemination of HIV-1 infection may occur before the generation of CTL responses. Viral avoidance of CTL recognition may occur through replication in immune-privileged sites, induction of immunosuppression, down-regulation of major histocompatibility complex class I or adhesion molecules on infected cell surfaces, or amino acid sequence ~ a r i a t i o nViral.~~ specific CTLs, including HIV-l-specific CTLs, have been implicated in pathologic processes,36,37 and some CTL responses may contribute to 'HIV-1-associated CD4 depletion or disease progression. Investigators have proposed that the generation and preservation of CD4 proliferative responses are necessary for the maintenance of high-level, biologically active HIV-1-specific CTLS~~; infection and depletion of CD4 T cells during the course of infection might abrogate the "helper" activity of these cells. The delayed production of HIV-1-specific CTL has been reported in infants.%,71 Although HIV-l-specific CTLs are often detected in adults within weeks of primary infection," they are uncommonly detected in infants younger than 6 months of age.% The delayed production of HIV-1-specific CTLs might contribute to the prolonged elevation of plasma viral load described in infants. CTLs are detected in the peripheral blood of most older children with established disease at frequencies similar to those described in Humoral Immunity-Neutralizing

Antibodies

Neutralizing antibodies are antibodies that prevent the productive infection of cells by plasma viruses. The potential role of neutralizing antibodies in viral infections is dependent on the extent to which cell-free virus contributes to viral spread, the extent to which high-affinity antibodies are generated, and the extent to which viral replication occurs at sites to which antibodies have poor access (reviewed in reference 67). Most HIV-1-infected individuals generate high titers of antibodies to several HW-1 gene products. Several neutralizing epitopes in gp120 have been mapped, but most of the early in vitro studies that evaluated antibody binding to gp120 used peptides or monomeric gp120; new data suggest that conformational epitopes are more biologically meaningful. Also, most early studies that assessed the ability of human sera and monoclonal antibodies to neutralize relied on the use of T-cell lineadapted viruses, which have subsequently been shown to be much more sensitive to neutralization than are primary isolates.24, 62 The rapid evolution of HIV-1 envelope gp120 genomic sequences over the course of HIV-1 infection suggests that neutralizing antibodies may exert selective pressures in vivo, although other selective pressures active on the HIV-1 envelope (e.g., tropism, therapy, or other immune responses) cannot be excluded. Although the administration of a highly active, HIV-1-specific monoclonal antibody protected SCID (severe combined immunodeficiency) mice against infection,3O the administration of a potent neutralizing monoclonal antibody did not protect monkeys against intravenous challenge with a primary HIV-1 isolate.= The evolution of a neutralizing humoral immune response following HIV-1

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infection has been primarily studied in adults.ss Neutralizing antibodies seem to develop slowly and are detected only after the decrease in plasma viremia following primary infection.n Broadly neutralizing antibodies begin to appear several months after primary infection. Broadly neutralizing antibody responses that persist over time have been described in many individuals experiencing long-term, nonprogressive HIV-1 infection.72,lo2 In vertically infected infants, Robert-Guroff et aln demonstrated that the presence of neutralizing antibodies directed against a clade B laboratory strain was correlated with clinical status. In a cross-sectional study, Broliden et all4 demonstrated that the presence of neutralizing antibodies correlated with better clinical status. Few studies of vertical HIV-1 infection have addressed the neutralization of patient isolates throughout the course of infection. I

HIV-1Specific Antibody-Dependent Cellular Cytotoxicity in Vertically Infected Infants

The authors have described the development of ADCC antibody responses in vertically infected infant~s.7~ HIV-1-specific ADCC antibody titers were serially measured from birth to 24 months in the plasma of 14 intrapartum-infected and 10 noninfected infants born to HIV-1-infected women. ADCC antibodies were detected in the cord blood of all infants, suggesting the efficient transplacental transfer of maternal antibodies. The mean ADCC antibody titers measured at birth in infected and noninfected infants were similar (10-3.9and l O - * O , respectively), suggesting that ADCC antibodies did not protect infants from the intrapartum transmission of HIV-1. In infected infants, ADCC titers at birth did not predict subsequent clinical disease course. The active production of HIV-1specific ADCC antibodies was detected in most infected infants only after 1 year of age, well after the loss of passively acquired maternal ADCC antibodies. The delayed detection of functional ADCC antibodies occurred despite evidence suggesting the active generation of envelope-specific antibodies as early as 4 months of age. The delay in functional ADCC antibody production is reminiscent of the ontogeny of antibodies to polysaccharide antigens ("Tindependent antigens") described in infants. Although antibodies to some polysaccharide antigens are generated at as early as 6 months of age, antibodies to most polysaccharide antigens are not produced efficiently until after 2 years of age. These data are compatible with data suggesting that most circulating HIV1 specific antibodies seem to be generated in response to virion debris rather than to native envelope expressed on the cell s~rface.6~ They are also compatible with studies suggesting that functional antibodies to HIV-1 envelope are generated in a T-independent manner.6 These studies demonstrated a delayed production of ADCC antibodies in young infants and the preferential recognition of strain-specific envelope epitopes. The delayed production of ADCC antibodies in infants may account, in part, for the less efficient control of viral replication and more rapid disease progression following vertical infection compared with adults. IMPLICATIONS FOR THE MANAGEMENT OF PATIENTS WITH VERTICAL HIV-1 INFECTION

The understanding of the kinetics of HIV-1 replication suggests that effective control of viral replication is essential to prevent immune attrition and the

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sequelae of HIV-1 infection, in turn suggesting that potent combination therapies should be initiated as early in infection as possible. Trials of intensive antiretroviral therapies in early vertical HIV-1 infection have been performed to address this hypothesis. These have included regimens composed solely of reverse transcriptase inhibitors (zidovudine, lamivudine, nevirapine; and zidovudine, lamivudine, nevirapine, abacavir; Pediatric AIDS Clinical Trial Group [PACTG] 356) and regimens combining reverse transcriptase inhibitors with protease inhibitors (zidovudine, lamivudine, ritonavir, PACTG 345, and didanosine, stavudine, nevirapine, nelfinavir, PACTG 356). All of these regimens have been well tolerated, and potent antiretroviral activity has been observed. Suppression of viral replication following the initiation of early combination antiretroviral therapy has been associated with normal growth and preservation of immune (Katherine Luzuriaga and John L. Sullivan, unpublished observations). In children with established disease, a question of enormous importance is, To what extent is HIV-1-induced immune deficiency reversible? Data from adult studies3,46 suggest that, over time, some immune responses might be restored following the control of viral replication. Data suggest that this may also be true in children. Several investigators have reported increases in peripheral blood following the initiation of potent antiretroviral therapies. In a cohort of children with advanced disease (Centers for Disease Control and Prevention Clinical Class C or Immune Category 317), Sleasman et alS have reported significant increases in CD4 T-cell counts following the initiation of therapy. Improvement in CD4 T-cell counts was especially pronounced in children less than 6 years of age. Additional studies are in progress to examine whether CD4 T-cell function improves together with CD4 T-cell numbers following the initiation of antiretroviral therapy. SUMMARY High-level viral replication is the primary determinant of CD4 depletion or disease development in HIV-1-infected children. The developing immune system of infants might allow for more efficient viral replication and less efficient immune containment of viral replication. Advances in the understanding of the pathogenesis of vertical HIV-1 infection suggest that the use of potent combination regimens to control HIV-1 replication offers the best opportunity to prevent or reverse the sequelae of HIV-1 infection.

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6. Binley JM, Klasse PJ, Cao Y, et al: Differential regulation of the antibody responses to gag and env proteins of human immunodeficiency virus type 1. J Virol 71:27992809, 1997 7. Biron CA, Byron KB, Sullivan J L Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320:1731-1735, 1989 8. Biti R, French R, Young J, et al: HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nat Med 3:252-253, 1997 9. Blanche S, Tardieu M, Duliege A, et al: Longitudinal study of 94 symptomatic infants with perinatally acquired human immunodeficiency virus infection: Evidence for a bimodal expression of clinical and biological symptoms. Am J Dis Child 144:12101215, 1990 10. Bleul CC, Wu L, Hoxie JA, et al: The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A 941925-1930, 1997 11. Borrow F, Lewicki H, Hahn BH, et al: Virus specific CI38+ cytotoxic T-lymphocyte activity associated with tontrol of viremia in primary human immunodeficiency virus type 1 infection. J Virol686103-6110, 1994 12. Borrow F, Lewicki H, Wei X, et al: Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 3:205-211, 1997 13. Brodie SJ, Lewinsohn DA, Patterson BK, et al: In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. National Medical L34-41, 1999 14. Broliden K, Sievers E, Tovo PA, et al: Antibody-dependent cellular cytotoxicity and neutralizing activity in sera of HIV-1 infected mothers and their children. Clin Exp Immunol 93:56-64, 1993 15. Brunell PA, Kotchman G S Zoster in infancy: Failure to maintain virus latency following intrauterine infection. J Pediatr 98:71-73, 1981 16. Bryson YJ, Luzuriaga K, Sullivan JL, et al: Proposed definitions for in utero versus intrapartum transmission of HIV-1 [letter]. N Engl J Med 3271246-1247,1992 17. Centers for Disease Control and Prevention: Revised classification system for HIV-1 infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep 43~1-10, 1994 18. Cheng-Mayer C, Seto D, Levy J A Altered host range of HIV-1 after passage through various human cell types. Virology 181:288-294, 1991 19. Chun TW, Carruth L, Finzi D, et al: Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387183-188, 1997 20. Clapham PR, Weiss RA. Spoilt for choice of co-receptors. Nature 388230-231, 1997 21. Clerici M, DePalma L, Roilides E: Analysis of T helper and antigen-presenting cell functions in cord blood and peripheral blood leukocytes from healthy children of different ages. J Clin Invest 91:2829-2836, 1993 22. Cocchi F, DeVico AL, Garzino-Demo A, et al: Identification of RANTES, MIP-la and MIP-1B as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811-1815, 1995 23. Conley A], Kessler JA, Boots LJ, et al: The consequence of passive administration of an anti-human immunodeficiency virus type 1 neutralizing monoclonal antibody before challenge of chimpanzees with a primary virus isolate. J Virol 70:6751-6758, 1996 24. Daar ES, Li XL, Moudgil T, et al: High concentrations of recombinant soluble CD4 are required to neutralize primary HIV-1 isolates. Proc Natl Acad Sci U S A 8765746578, 1990 25. Dean M, Carrington M, Winkler C, et al: Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856 1862, 1996 26. Dickover R, Dillon M, Gillette S, et al: Rapid increases in load of human immunodeficiency virus correlate with early disease progression and loss of CD4 cells in vertically-infected infants. J Infect Dis 1701279-1284, 1994

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