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Originally published online as doi:10.1189/jlb.0403186 on August 21, 2003

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(Journal of Leukocyte Biology. 2003;74:657-666.)
© 2003 by Society for Leukocyte Biology

HIV-1 fitness and macrophages

Maureen M. Goodenow*,{dagger},1, Stephanie L. Rose*, Daniel L. Tuttle* and John W. Sleasman{ddagger}

* Department of Pathology, Immunology, and Laboratory Medicine and
{dagger} Department of Pediatrics, Division of Immunology and Infectious Diseases, University of Florida College of Medicine; and
{ddagger} Department of Pediatrics, Division of Allergy and Immunology, University of South Florida College of Medicine, and All Children’s Hospital, St. Petersburg, Florida

1 Correspondence: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Box 100275, 1600 SW Archer Road, Gainesville, FL 32610. E-mail: goodenow{at}ufl.edu


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ABSTRACT
 
HIV-1 comprises a collection of closely related, but not identical, viruses or quasispecies. Fitness represents a selective advantage for propagation among populations of organisms competing in a particular environment and is an important characteristic of viruses because of a link between fitness and pathogenesis. Environmental differences based on the type of cell that is targeted for infection or the cell type that produces virus, impact fitness. CD4-expressing cells of lymphocyte or macrophage lineage are the principal host cells for HIV-1, although the milieu in lymphocytes is distinct from the macrophage environment from the perspective of cell half-life and activation, signal transduction and expression of coreceptors, and bioavailability of antiretroviral drugs. Multiple viral determinants, including entry via envelope glycoproteins, replication by reverse transcriptase, and virion maturation by protease activity, contribute to fitness in different cells and provide targets for current antiretroviral therapies. This review focuses on fitness of HIV-1 in macrophages and examines the impact of protease inhibitors on fitness of quasispecies and an unexplained discordance between fitness and pathogenesis.

Key Words: review • antiretroviral therapy • gag/protease • envelope • tropism • phenotype


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INTRODUCTION
 
From an evolutionary perspective, fitness represents a selective advantage for propagation among populations of organisms competing in a particular environment. As applied to RNA viruses, including HIV-1, fitness is interrelated with, but not absolutely equivalent to, replicative capacity [1 ]. Competition is a key element of fitness because how individual viruses replicate unchallenged may be independent of fitness when populations of viruses compete in the same environment.

Fitness or competitive advantage among viruses within infected individuals has significance because HIV-1 comprises a collection of closely related, but not identical, viruses or quasispecies [2 3 4 5 ]. During virus replication within host cells, the virion-associated diploid RNA genome is reverse transcribed into DNA by a viral-encoded enzyme, reverse transcriptase (RT) [6 ]. RT lacks proofreading or editing functions resulting in misincorporation of nucleotides during every cycle of viral DNA synthesis. Recombination or duplications/deletions of viral sequences mediated predominantly by RT can also occur during replication. Within an infected individual, millions of virus variants are produced at any time [7 ]. Changes in environmental pressures select viral variants or quasispecies that evolve and fluctuate throughout the course of infection within the host [8 ].

Fitness represents an important characteristic of viruses because of the link between fitness and pathogenesis. High-level viral replication in individuals is a key prognostic indicator for poor clinical outcome [9 ]. Conversely, suppression of virus replication generally delays or reverses clinical disease progression. Multiple selective factors, including host genetics or immunity [4 , 10 11 12 ], target cell availability [13 14 15 ], and virus genotype [16 17 18 ], as well as antiretroviral therapies (ARTs), can contribute to diminished fitness of viruses [19 20 21 22 ] and, by extension, improved clinical prognosis. For a variety of reasons, suppression of virus replication within infected individuals is often incomplete, leading to emergence of drug-resistant quasispecies, which display increased fitness and diminished sensitivity to inhibition, and are linked to accelerated loss of CD4 T cells and disease progression in the host [23 24 25 ].

The paradigm of viral fitness or replicative capacity and pathogenesis has two important exceptions. One exception is related to clinical outcomes when simian immunodeficiency virus (SIV), a primate lentivirus related to HIV-1, infects different hosts [26 27 28 ]. Levels of viremia produced by SIVAGM or SIVSM in African green monkeys (AGM) or sooty mangabeys (SM), respectively, can reach levels as high as during disease progression in HIV-infected individuals, but produce no immune pathogenesis in the natural hosts. In contrast, when SIV is introduced into macaques, high levels of virus replication produce rapidly fatal immune suppression. Host factors are major contributors to attenuation of pathogenesis by the same virus replicating in different primates [29 30 31 ]. The second important exception to a direct relationship between fitness and pathogenesis of viruses can occur with ART that includes combinations of RT and protease inhibitors (RTI or PI, respectively). Drug-resistant quasispecies of HIV-1 that replicate to high levels and outcompete wild-type, drug-sensitive viruses emerge frequently in infected individuals in response to combination ART, which usually indicates continued clinical decline. Yet, drug-resistant viruses that display significant fitness in vivo, but fail to suppress CD4 T cell reconstitution or accelerate disease, emerge in some ART-treated individuals [32 33 34 35 36 ]. Mechanisms that contribute to discordant viral failure and immune success (VF/IS) response are unexplained, but might include both host factors (such as receptors, signal transduction pathways, cellular activation, or cell cycle stage) and viral factors (including accessory genes, gag/pol genotype, and tropism).

Pharmacological perturbations of the environment provide powerful tools to determine regions of the viral genome, which are required for adaptation and fitness and could be targeted for development of novel drugs. Defining molecular determinants of HIV-1 fitness has implications for understanding transmission of the virus, development of drug resistance, and interactions at the cellular level with lymphocytes and macrophages, the principal cellular targets for HIV-1 infection and replication. This review focuses on replicative capacity and fitness of HIV-1 in macrophages and examines the impact of protease inhibitors on fitness of quasispecies and an unexplained discordance between fitness and pathogenesis.


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HIV-1 AND MACROPHAGES
 
In general, lentiviruses display a propensity for infection and replication in macrophages. In fact, manifestations of pathogenesis by some nonprimate lentiviruses occur exclusively in macrophages [37 ]. Primate lentiviruses maintain an ability to target macrophages but have an expanded host cell range that includes lymphocytes and a variety of other hematopoietic cells that express CD4 and appropriate coreceptors. Multiple lines of evidence implicate macrophages directly as a cellular source of HIV-1. For example, infection of a variety of cells of monocyte/macrophage lineage, such as macrophages in lymphoid tissues [38 39 40 41 42 43 ], peripheral blood monocytes [40 , 44 45 46 47 ], alveolar macrophages [48 49 50 ], brain microglia [51 ], or Langerhans cells [52 53 54 ] occurs within patients, in culture, and in animal models [55 56 57 58 ]. Although a contribution by macrophages to cell-free plasma virus is estimated to be less than 1% [59 ], direct measures of macrophage-derived viruses in plasma within infected individuals are difficult. Viruses produced from macrophages or T lymphocytes can be distinguished by the host proteins CD36 or CD26, respectively, which are incorporated into virions during budding [60 ]. On the basis of the distinguishing characteristics of virion-associated host cell proteins, opportunistic infections can increase the proportion of macrophage-derived virus to 10% or greater of plasma virus levels [61 , 62 ].

Macrophages provide an environment for HIV-1 that is distinct from the milieu in lymphocytes. In contrast to lymphocytes, monocyte-derived macrophages (MDM) are in a stage of terminal differentiation and have a limited potential for proliferation [63 ]. Although a majority of infected lymphocytes turn over rapidly (days) [41 , 59 ], macrophages survive HIV-1 infection for long periods (weeks to months) [64 ], produce significant amounts of virus [64 ], and most likely constitute one of the long-lived reservoirs for virus replication in infected individuals [65 , 66 ]. Signal transduction pathways in macrophages and T lymphocytes are inherently different, can be modulated by HIV-1, and contribute to regulation of cell susceptibility to infection [67 68 69 70 71 ]. In particular, different CD45 isoforms, which are important for regulating biological function and signaling [72 ], are expressed by naïve and memory subsets of CD4 T lymphocytes, while p56lck, a signal transduction molecule associated with CD4 in T lymphocytes, is absent from macrophages [73 ]. Viruses produced by macrophages can differ in infectivity from viruses produced by lymphocytes [74 ]. The virus replication cycle in macrophages relative to lymphocytes can require extended time because of limitations of nucleotide precursors in macrophages [14 ]. Yet, some virus strains replicate with similar kinetics in both macrophages and lymphocytes [13 ] and levels of replication by primary isolates in macrophages can exceed levels of virus produced by lymphocytes [56 , 75 ]. Consequently, environmental differences, based on the type of cell that is targeted for infection or the cell type that produces the virus, set up conditions that impact fitness.

Macrophage tropism and fitness
Tropism, that is the range of host cells supporting virus replication, is regulated at both entry and postentry levels. Entry into cells by HIV-1 is mediated by target cell expression of CD4 and appropriate chemokine receptor(s), predominantly CCR5 or CXCR4 [53 , 76 77 78 ]. Prior to discovery of coreceptors, variants of HIV-1 were classified by an ability to induce syncytium (SI) or not (NSI) in the MT2 T cell line [79 , 80 ]. In general, SI characteristics of viruses correspond to use of CXCR4 (X4 viruses), while NSI viruses use CCR5 (R5 viruses) (Table 1 ). CD4 cells that express CCR5 include a small subset of activated memory T lymphocytes, as well as macrophages, while CXCR4 is expressed by most CD4 T lymphocytes, by transformed cells of lymphocyte or monocyte lineages, and by macrophages (Table 1) . R5 viruses are invariably macrophage (M)-tropic and display an M-R5 phenotype. In contrast, SI/X4 viruses display heterogeneous phenotypes. A majority of primary SI/X4 viruses replicate efficiently in both macrophages and T cell lines, use CXCR4 either alone or in combination with CCR5, and are dual (D)-tropic [56 , 75 , 76 , 81 , 82 ], while X4 viruses that fail to display tropism for macrophages, but maintain an ability to replicate in T cell lines, have a T-X4 phenotype.


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  		Table 1. Phenotype of HIV-1 Based on Coreceptor Use, V3 Charge, and Tropism

Host cells provide an environment that can impact fitness of viruses. In growth competition with NSI/R5 viruses, SI/X4 viruses can display greater fitness in T cell lines, as well as in primary CD4 T lymphocyte populations, which express CXCR4 more frequently than CCR5 [83 ]. Macrophages can provide an alternative perspective of fitness. For example, SI/X4 (T-X4) viruses competing with NSI/R5 (M-R5) viruses in MDM cultures would no longer exhibit the fitness advantage displayed in either PBMC or T cell lines. In addition, macrophage tropism can distinguish fitness between competing dual tropic and T-X4 viruses, which display otherwise comparable fitness in CD4 T lymphocytic cells. Expression of coreceptors by cells is linked to viral fitness.

Viral envelope determinants of macrophage tropism
Although multiple viral determinants mediate macrophage tropism at a variety of steps in the virus life cycle [84 85 86 ], viral envelope glycoproteins are major factors regulating entry [55 , 87 ]. Envelope glycoproteins that mediate entry by CCR5 or CXCR4 display significant differences in charged amino acid residues in the V3 hypervariable domain of Env gp120 (Table 1) . R5 envelopes have V3 domains that range in net charge between +2 and +4, reflecting both acidic (aspartate and glutamate) and basic (arginine and lysine) amino acids. In contrast, X4 V3 domains display net charge >= +5, which results from reduced frequency of acidic amino acids, as well as increased numbers of basic residues. Both total number and location of charged residues can distinguish between V3 domains that use R5 or X4 [88 89 90 ]. In general, use of CCR5 on PBMC and macrophages or CXCR4 on PBMC and T cell lines maps predominantly, if not exclusively, to V3 [91 92 93 94 95 ]. In contrast, envelopes that mediate entry into macrophages via CXCR4 have additional determinants over and above V3 domains with net charge >= +5. D-X4 viruses have isoleucine, whereas T-X4 viruses have methionine at amino acid position 326 in V3 [88 ] (Table 1) . Whether or not amino acid 326 is a biomarker or impacts directly viral gp120 engagement of the CXCR4 coreceptor on macrophages requires investigation. V1 and V2 hypervariable domains in Env gp120 can display more genetic diversity than V3 [96 ], are implicated in a variety of studies as determinants of macrophage tropism [91 , 97 98 99 ], and contribute to an ability by virus to use CXCR4 on macrophages [100 ].

Macrophage fitness and pathogenesis
V3 charge, coreceptor use, viral phenotype, and fitness evolve within individuals during the natural history of HIV-1 infection [101 ]. For example, M-R5 viruses with low V3 charge tend to establish new infections in individuals [78 , 102 , 103 ]. Multiple studies identify evolution of X4 viruses with increasing V3 charge, as well as persistence of viruses from both the R5 and X4 lineages, within infected individuals [56 , 104 105 106 ] (Fig. 1 ). Differences in fitness are apparent late in infection when viruses that use CXCR4—the coreceptor expressed by a majority of CD4 T lymphocytes—have a selective advantage over viruses that use CCR5, which is expressed by a small subset of activated memory CD4 T cells that are most susceptible to infection and death during acute and chronic infection [66 , 107 , 108 ].



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  		Figure 1. Evolution of envelope and phenotype in vivo. Most HIV-1-infected individuals initially express in blood virus strains that have low V3 net charges (+2 to +4) and utilize CCR5 as coreceptor. Often, evolution of envelope occurring during the natural history of HIV-1 disease or ineffective ART gives rise to viruses with high net charge (>=+5) that utilize CXCR4, which tend to be more pathogenic. This representative phylogenetic tree indicates separate lineages that are generally observed for low- and high-charged V3 domains and consequent changes in phenotype are indicated.

SI/X4 viruses are classified as pathogenic, based on a significant decline of CD4 T cells and clinical disease progression that occurs concomitant with or immediately following emergence of high levels of X4 quasispecies in peripheral blood [56 , 79 , 80 , 109 110 111 ]. Many SI/X4 viruses that evolve in patients with advanced disease maintain a capacity to replicate in MDM, implicating dual-tropic viruses in pathogenesis. Yet, almost half of adults and a majority of pediatric patients develop advanced disease without detectable SI/X4 quasispecies in their peripheral blood, indicating that fitness of NSI/R5 viruses in vivo and ex vivo is also related to pathogenesis [56 , 83 , 112 113 114 115 116 ]. One characteristic that can distinguish among M-R5 viruses is a range of levels of replication in macrophages. R5 viruses from individuals in late-stage disease display increased replication in MDM cultures in comparison to restricted replication in MDM by R5 viruses isolated during acute or early infection, or over the course of chronic infection in individuals who remain asymptomatic for years [56 , 75 ]. Overall, replicative capacity in macrophages can be a significant marker for pathogenic viruses independent of coreceptor preference [116 ], implicating viral determinants in addition to envelope as contributors to viral fitness.


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ART AND MACROPHAGES
 
Antiretroviral drugs approved for treatment now target multiple steps in the virus life cycle, including fusion, reverse transcription, and protease (PR) processing required for infectivity of virions. Although antiretroviral drugs are highly effective in reducing transmission of virus from mother to child and controlling virus replication in infected individuals [117 , 118 ], incomplete suppression results in emergence of quasispecies with diminished susceptibility to inhibitors. Fitness of drug-resistant viruses in a quasispecies is related directly to the environment. Removal of drugs results in rebound by drug-sensitive viruses that outcompete drug-resistant viruses [119 120 121 122 ].

Lymphocytes and macrophages provide distinct milieus for effectiveness of antiretroviral inhibitors. For example, nucleoside RTIs are highly effective in macrophages compared with lymphocytes, whereas non-nucleoside RTIs have approximately equivalent activity in both types of cells, reflecting different mechanisms of inhibitor action and nucleoside pools within cell types [123 ]. In contrast, PI suppression of virus replication in macrophages requires significantly increased levels of inhibitor compared to the levels that are effective in lymphocytes [64 , 123 124 125 ]. Reduced activity of PI in MDM could reflect reduced uptake or bioavailability, as well as slower replication kinetics by viruses in MDM.

Viral determinants of therapy escape
Viral escape from antiretroviral drugs occurs primarily by selection for amino acid changes in regions of the viral genome targeted by the drug. For example, sensitivity to the fusion inhibitor T20 is determined primarily by sequences in the N-terminal helical domain of envelope gp41 [126 ], while reduced sensitivity to RT or PR inhibitors involves amino acid changes in RT or PR, respectively [2 , 127 ]. A direct relationship between genotype and phenotype in viral quasispecies that have reduced sensitivity to inhibitors can be obscured because other regions of the viral genome, in addition to the direct targets, also contribute to therapy escape. For example, determinants of CCR5 or CXCR4 coreceptor use in Env gp120 independently modulate viral sensitivity to T20 [128 , 129 ], which reflects functional interactions between gp120 and gp41 that are required for viral entry into cells. Likewise, functional interactions between PR and regions of Gag, including the cleavage sites that are substrates for PR activity, are essential for processing Gag-Pol polyproteins during virion maturation. Sequences in Gag, including nucleocapsid p7, p6, and cleavage sites, modulate enzymatic activity of PR and contribute to replicative capacity by quasispecies from infected individuals prior to therapy [19 , 21 , 130 131 132 133 134 135 ]. During the course of ART, accumulations of mutations in PR that reduce sensitivity to drugs are accompanied by amino acid changes in Gag and /or cleavage sites. The changes are important because of a direct contribution to replicative capacity and fitness of viruses, primarily in lymphocytes [19 , 21 , 127 , 130 131 132 , 134 135 136 137 138 139 140 141 ]. Determinants in Gag required for fitness by viruses with PR resistance are virtually unstudied in macrophages.

ART and fitness
Fitness of HIV-1 as related to reduced sensitivity to inhibitors can be assessed in vivo within infected individuals, ex vivo by virus isolates, or by recombinant molecular clones replicating in a variety of host cells [3 , 20 , 142 143 144 ]. Fluctuations of quasispecies in plasma and PBMC competing within individuals prior to and during treatment provide the most direct evaluation of viral fitness and viral dynamics in different compartments. Nonetheless, unraveling the interrelationship among multiple variables, including bioavailability of drugs, host genetic factors and immune responses, and viral determinants, which can contribute to evolution of viral fitness within individuals, is complicated. Primary viral isolates from infected individuals can be evaluated for fitness ex vivo in culture assays, which reduce the contribution to fitness by some variables, such as host immune response, although culture environments provide alternative selective pressures that perturb the quasispecies. An alternative approach to evaluation of fitness involves using recombinant viruses that are constructed with the region of interest, for example, specific PR or RT alleles from viruses in individuals treated with combinations of RT and/or PR inhibitors. An advantage to the recombinant virus approach is that defined regions from different viruses from different individuals can be studied in a constant genetic background, although the predominant molecular clones used for construction of recombinant viruses have T-X4 envelopes, which restrict entry to CXCR4-expressing CD4 T lymphocytes and T cell lines.

To address the question of fitness in macrophages, as well as in CCR5-expressing lymphocytes, compared with CXCR4-expressing lymphocytes, we developed two recombinant viruses based on the HIVLAI molecular clone [145 ], one with Env gp120 V1 to V5 from HIVLAI (T-X4) and a second with gp120 V1 to V5 from HIVJRFL (M-R5). Replication competent, T-X4 and M-R5, gag/PR recombinant viruses were constructed by exchanging gag/PR of HIVLAI with gag/PR from viruses within an infected individual prior to and following combination ART [131 ]. Pre-therapy PR alleles contained no natural polymorphisms that might alter sensitivity to inhibitors [33 , 130 ], while post-therapy gag/PR alleles included multiple mutations as a result of ritonavir treatment that failed to sustain virus suppression. Replicative capacity by post-therapy gag/PR recombinant viruses was diminished in both CCR5- and CXCR4-expressing CD4 lymphocyte subsets. In contrast, when R5 recombinant viruses were directed to macrophages, pre- and post-therapy gag/PR viruses replicated to similar levels [146 ].

Modulation of replicative capacity by recombinant viruses maps to mutations in Gag and/or PR because all recombinant viruses contained the HIVLAI RT allele [131 ]. Post-therapy Gag/PRs have slowed processing kinetics (O’Brien, Goodenow, and Dunn, unpublished results) [19 , 21 , 134 , 135 ], which would decrease production of mature virions from lymphocytes, where the viral replication cycle proceeds at a higher rate than macrophages. In macrophages, the virus replication cycle is extended, and reduced processing kinetics by post-therapy, drug-resistant Gag/PR may not be rate limiting for production of mature virions [14 ].

Impact by therapy on fitness and pathogenesis
Combination antiretroviral therapies can have a dramatic impact on viral replication and disease progression in individuals. Successful suppression of virus replication usually results in increased levels of CD4 T lymphocytes (viral and immune success, VS/IS) (Fig. 2A ). Inadequate control of virus replication results in rebound of viruses with multiple mutations that increase fitness in the presence of drugs and a failure to reconstitute CD4 T cells (viral and immune failure, VF/IF) (Fig. 2B) . Pre- and post-therapy viruses in VF/IF patients appear equally pathogenic because no increase in CD4 T cell numbers occurs. Linkage between viral and immune success (VS/IS) or failure (VF/IF) in response to combination ART is predictable. An unexpected outcome of ART occurs occasionally in adults and frequently in children and adolescents, who experience significant and sustained improvement in CD4 T cell numbers (immune success), even though plasma virus levels are suppressed only transiently in response to combination therapy (viral failure) (VF/IS) (Fig. 2C) . An alternative discordant response, suppression of virus without CD4 T cell rebound (VS/IF) (Fig. 2D) , is displayed by some adults, but less frequently by children who have greater potential than adults for immune reconstitution [32 , 33 , 35 , 147 148 149 150 ].



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  		Figure 2. Outcomes in patients to combination antiretroviral therapy based on plasma virus levels and CD4 T cell numbers. (A) VS/IS. Viral success is based on sustained reduction of plasma virus levels to <400 copies per ml. Immune success indicates a reconstitution of CD4 T cell numbers. (B) VF/IF. Viral failure and immune failure are based on transient and incomplete suppression of plasma virus and no increase in CD4 T cells. (C)VF/IS. Discordant response to therapy involves transient and incomplete suppression of plasma virus, but sustained increase in CD4 T cells [33 ]. (D) VS/IF. Alternate discordant response to therapy involves sustained reduction of plasma virus levels and no increase in CD4 T cells. Solid line denotes median log10 RNA copies per milliliter of plasma indicated on left axis; dotted line denotes median CD4 T cell counts per microliter of blood indicated on right axis.

Post-therapy viruses that develop in patients with a discordant VF/IS response display replicative capacity that is similar to viruses in individuals with a VF/IF response [33 ]. Although plasma viruses that rebound during ART in VF/IS patients can reach levels that are similar to pretherapy plasma virus levels, pre- and post-therapy viruses may differ in fitness at least for certain subsets of target cells [151 ]. For example, replication by post-therapy, drug-resistant viruses in thymocyte culture is restricted [152 ]. Diminished replication may extend to peripheral lymphocytes, which would limit cell death, contribute to increased CD4 T cell numbers, and predict a reduction in cell-associated virus in peripheral lymphocytes. The dramatic and sustained restoration of CD4 T cells experienced by VF/IS individuals could result from viruses attenuated for pathogenesis. If viruses that emerge in discordant responses have diminished fitness in lymphocytic cell lineages, then identifying cellular source(s) of high levels of viruses in the plasma of VF/IS individuals is critical. One possibility is that the contribution to plasma viremia by macrophage-derived drug-resistant viruses increases during therapy in VF/IS responses. Persistent virus production by drug-treated macrophages implicates macrophages as sanctuaries for virus replication and evolution of drug resistance in treated individuals.


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QUESTIONS AND FUTURE DIRECTIONS
 
The focus of this review is on macrophage tropism, viral determinants in Env that mediate entry into macrophages, and the role of macrophages in persistent production of virus in antiretroviral-treated individuals. VF/IS response shows that virus replication and fitness can be unlinked from pathogenesis. Diminished pathogenesis might be linked to a general reversion of post-therapy viral quasispecies to M-R5 viruses, or to genetic determinants outside the envelope that contribute to replication capacity and/or an impact by viruses on CD4 T cells. Virus interactions with macrophages following entry are determined by a variety of proteins encoded by multiple accessory genes in the viral genome, and by host factors. Currently, little information about specific host proteins that might facilitate viral fitness in macrophages or distinguish between macrophages that are permissive or restrictive for virus replication is available. Most studies of interactions between HIV-1 and macrophages focus on subtype B strains. Prevalence of other subtypes throughout the world necessitates expanding studies of viral fitness and macrophage tropism to include viruses that are involved in the majority of infections. Persistent virus production by macrophages, even with antiretroviral therapies that reduce levels of infection in lymphocytes, provides a challenge to the development of drugs that have increased effectiveness for one of the long-lived reservoirs of virus.


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ACKNOWLEDGEMENTS
 
The authors receive funding from PHS awards HD32259, AI47723, AI47734, HL58005, and T32 AR07603; the Elizabeth Glaser Pediatric AIDS Foundation; Seed Grant and Young Investigator Grants from the American Lung Association of Florida; Laura McClamma Fellowship Award.

Received April 25, 2003; revised July 15, 2003; accepted July 26, 2003.


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