Use of Contaminated Blood Products
In the United States, the American Red Cross began testing donated blood for antibodies to HIV-1 in 1985; in 1992, this program was expanded to include testing for HIV-2. In 1992 and 1993, the risk of transfusion-acquired HIV in the United States was less than one case of HIV for every 450,000 to 600,000 donations of screened blood, with almost all of the risk related to donors who were infected with HIV shortly before donating their blood and who had not yet undergone seroconversion.34 With current enzyme immunoassay serologic tests, this so-called window period typically lasts until about day 25 after HIV infection. In 1996, HIV p24 antigen testing was mandated; this test further decreased the risk of HIV transmission. More recent attempts have used nucleic acid testing as an even more sensitive assay to detect donors during the window period. In an interesting case report, a 13-year-old boy received a blood transfusion 2 days before it was discovered that the donor had acute HIV syndrome. The boy received a three-drug antiretrovi-ral postexposure prophylaxis regimen for 9 months and repeatedly tested negative for HIV RNA antibodies, even when tested 6 months after antiretroviral postexposure prophylaxis was dis-continued.35 In China, unsafe blood donation techniques (i.e., reuse of contaminated phlebotomy equipment) led to the infection of some Chinese communities in the 1990s.12
Mother-to-Child Transmission
Mother-to-child transmission of HIV accounts for a substantial proportion of HIV cases in developing countries. Such transmission can occur during gestation, at the time of delivery, or post partum via breast-feeding. In the absence of antiretroviral therapy, mother-to-child transmission rates generally range from 20% to 30%,36 with higher rates occurring in developing countries and in women who breast-feed. Multiple studies have clearly shown the presence of HIV RNA in the mother to be a strong predictor of transmission.37,38 In addition, in HIV-infected mothers who were not receiving antiretroviral therapy, cesarean section decreased the risk of transmission by about 50%.39 Although HIV transmission from mother to child can occur early in pregnancy or post partum,40-42 available data suggest that most perinatal HIV transmission occurs near or at the time of delivery.41 The widespread use of antiretroviral therapy to prevent mother-to-child HIV transmission has led to a dramatic decline in perinatal HIV transmission in developed countries.3641 Current recommendations for the use of antiretroviral therapy to prevent mother-to-child HIV transmission are discussed elsewhere [see Antiretroviral Therapy to Prevent Perinatal Transmission, below].
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Occupational Exposure
As of July 1, 2000, the CDC had reported 56 documented cases of occupational HIV transmission and an additional 138 cases of possible occupational HIV transmission.2 Of the 56 documented cases, 48 (86%) involved a percutaneous exposure, five (9%) involved a mucocutaneous exposure, two (4%) involved both percutaneous and mucocutaneous exposures, and one (2%) occurred by an unknown route of exposure. In addition, 49 of the 56 cases (88%) involved exposure to blood from an HIV-infected individual. On the basis of available data, the average risk of HIV transmission to a health care worker who experiences a percutaneous exposure to HIV-infected blood but who does not receive postexposure prophylaxis is approximately 0.3%; the risk associated with a mucous membrane exposure to HIV-infected blood is approximately 0.09%.® There are no documented cases of HIV transmission in health care workers that resulted from exposure to intact skin. Risk factors associated with increased risk of transmission include deep needle-stick injuries, use of hollow-bore needles, use of a device visibly contaminated with blood, exposure events involving the transference of a large volume of blood, a needle-stick injury in which the needle had been placed directly in an artery or vein of an HIV-infected patient, and the source patient having advanced AIDS.43 The relative risk of transmission in terms of the source patient’s HIV RNA level has not been established for occupational HIV transmission.
Pathogenesis and Progression of Disease
HIV Structure and Life Cycle
HIV is a member of the lentivirus family of retroviruses. On electron microscopy, HIV appears as spherical particles that are approximately 110 nm in diameter, with knoblike projections on the surface of the virus and a cone-shaped viral core44 [see Figure 3]. HIV particles contain two copies of an RNA genome, each of which is approximately 10,000 base pairs in length and encodes nine genes.
The genetic structure of HIV-1 is similar to that of all retro-viruses. The genome is organized into three major regions (gag, pol, and env) that are flanked by the HIV-1 promoter or long terminal repeat. The gag region contains the structural genes for HIV (i.e., matrix, capsid, nucleocapsid, and two small peptides), the pol region contains the genes for the viral enzymes needed to carry out the life cycle (i.e., reverse transcriptase, integrase, and protease), and the env region encodes the genes for the viral envelope proteins (i.e., gp160, which is cleaved to gp120 and gp41).45
HIV-1 has six regulatory genes that are vital for its life cycle and pathogenicity: tat (the transactivating gene) upregulates transcription of the genome; rev coordinates the expression of the regulatory and nonregulatory genes by orchestrating the transport of spliced and unspliced RNA transcripts out of the nucleus; nef helps the virus evade the host immune response by downregulating expression of CD4 and major histocompatibili-ty complex (MHC) class I molecules on the cell surface and also contributes to viral virulence; vpu reduces host cell CD4 expression and is involved in cellular release of virions; vpr is important for infection of nondividing cells by facilitating nuclear localization of the viral preintegration complex and also regulates cell cycle arrest; and vif is important for virion assembly, infec-tivity, inactivation of the host cell antiviral factor APOBEC3G,46 and gp120 membrane insertion.47 The reverse transcriptase of HIV is very error-prone and introduces mutations at a rate of approximately 1 in 104, or about one mutation in every virus produced. In addition, during normal replication, the reverse transcriptase enzyme jumps from one strand of nucleic acid to another to complete the synthesis of daughter strands. This strand-jumping enables recombination between different viral strains infecting the same cell. Mutation and recombination permit the virus to respond rapidly to environmental changes such as those related to receptor availability, host immune responses, and antiretroviral drugs.
Two different HIV species have been identified: HIV-1 and HIV-2. Those isolates of HIV-1 that have been globally identified can be classified into the three major phylogenetic groups: M (main), N (neither M nor O), and O (outlier).4,48 The M group has predominantly been responsible for the global HIV epidemic. This group can be further subdivided into 10 distinct subtypes or clades, termed subtypes A to J. Patients can be infected with more than one clade, and recombination of viruses from different clades can occur.
The life cycle of HIV is similar to that of other retroviruses. Understanding the life cycle is important for understanding both cellular pathogenesis and the targets of current and future anti-HIV therapies. The first step in the life cycle involves attachment of the virus to the host target cell. The first point of interaction consists of the binding of the HIV envelope surface protein (gp120) with the CD4 receptor on the host cell [see Figure 4]. For infection to proceed, cellular coreceptors must also bind gp120, causing its release and the subsequent exposure of the other HIV envelope protein, gp41. The gp41 protein mediates fusion of the virus and cell membranes by stabbing the cell membrane and undergoing a conformational change that brings the two membranes in contact, facilitating fusion and viral entry.
Although investigators have discovered numerous corecep-tors that can potentially bind HIV, the coreceptors CCR5 and CXCR4 appear to play the most important role.49 CD4+ T cells express both CCR5 and CXCR4 receptors, whereas monocytes predominantly express CCR5 [see Figure 5]. Available data suggest that initial HIV infection predominantly involves R5 strains of HIV. There is significant genetic variation in the CCR5 corecep-tor, and some individuals who are homozygous for a CCR5 deletion mutation (a 32-base-pair deletion) can be repeatedly exposed to HIV without becoming infected.50 Individuals who are heterozygous for this A32 mutation are not protected against HIV infection but may initially manifest a slower rate of disease progression [see Figure 6].
After the fusion of the viral and cellular membranes, the viral capsid enters the cell [see Figure 7] and the HIV reverse transcrip-tase enzyme converts the single-stranded HIV RNA into a double-stranded DNA called proviral DNA. The provirus is then integrated into the host cell chromosome by the viral enzyme inte-grase.
Figure 4 This illustration shows the major steps involved in HIV binding to and entering the host cell. After binding to the fusion domain, the membranes merge.
Subsequently, cellular enzymes transcribe the provirus into spliced and nonspliced messenger RNA (mRNA) molecules that encode the regulatory genes (tat and rev) and the structural genes and that serve as full-length genomic transcripts. This process proceeds in an organized fashion with the regulatory genes tat and rev (on spliced transcripts) expressed first, followed by the transport of full-length transcripts into the cytoplasm, which are then translated into the structural proteins or which serve as genomic RNA for progeny virus. The late stages of viral replication involve both the assembly of the viral particles, with each viral core incorporating two copies of the viral RNA genome, and the budding and release of the virus from the cell surface. The HIV protease enzyme plays an important role in this late process by cleaving the gag polyprotein into smaller functional components, which allows for the formation of mature, infectious viral particles.
Figure 5 R5 strains preferentially bind to CC chemokine receptor-5 (CCR5) coreceptors that are present on both monocytes and CD4+ T cells. R4 strains preferentially bind to CXC chemokine receptor-4 (CXCR4) coreceptors (predominantly on CD4+ T cells).
Figure 6 This diagram shows the relationship of genetic diversity of the CCR5 coreceptor to progression of and susceptibility to HIV infection.
Early events and disease progression
Worldwide, most HIV infections occur by sexual transmission across mucosal surfaces. The R5 viruses are preferentially transferred across epithelial cell membranes,51 where they may encounter dendritic cells, CD4+ T cells, or macrophages.52 HIV may productively infect any of these cell types or be tethered to dendritic cells by means of DC-SIGN (dendritic cell-specific ICAM [intercellular adhesion molecule]-grabbing nonintegrin) or other C-type lectin receptors (CLRs).53,54 HIV infection of CD4+ T cells is enhanced when the virus is captured and presented to the T cells by dendritic cells expressing DC-SIGN or other CLRs.55-57 Locally infected T cells or dendritic cells coated with HIV then traffic to regional lymph nodes, where the virus propagates rapidly in the abundant CD4+ T cell pool before dissemi-nating.58 At this point, patients may experience symptoms of an acute retroviral syndrome before mounting a cytotoxic T cell (CTL) response that partially controls viral replication.59 However robust this CTL response may be, it never eradicates the infection, in part because the virus preferentially infects and kills the CD4+ T cells that are recruited to the site of HIV replication.® This selective depletion of HIV-directed CD4+ T cells cripples the effectiveness of HIV-directed CD8+ T cells, which rely on CD4+ T cell help for proper functioning. Furthermore, the high mutation rate of the virus allows it to escape the control of most potent immune responses. As a result, the infection persists, and continued rounds of replication lead to the gradual depletion of all CD4+ T cells. At the same time, a subset of activated, HIV-infect-ed CD4+ T cells returns to a quiescent state, remains latently infected, and persists with a half-life of up to 44 months.61 This latent reservoir of HIV can reactivate even after years of suppres-sive antiviral therapy.62-64
The plasma HIV RNA level is a strong independent predictor of the progression to AIDS in untreated HIV-infected persons [see Figure S].65 In essence, the higher the HIV RNA level, the more rapidly the disease will progress. For example, in patients with a CD4+ T cell count greater than 500 cells/^l, about 5% of those who have a baseline HIV RNA level of less than 500 copies/ml will develop AIDS within 6 years, compared with 67% of those who have a baseline HIV RNA level of greater than 30,000 copies/ml. In contrast, the CD4+ T cell count provides an accurate way to assess the current immunologic status.
Figure 7 This illustration depicts the major steps in the life cycle of HIV.
Figure 8 This graph shows the risk of progression to AIDS at 6 years and the relationship of risk of progression to HIV RNA values and CD4+ T cell counts.
Within 6 months of primary HIV infection, the plasma level of HIV appears to reach a fairly constant level—a level referred to as the set point. The set point is determined by a number of host and viral factors and varies from person to person. The HIV-directed CTL response appears to be the most important factor in determining the HIV set point. Indeed, the development of the HIV CTL response coincides with the initial decline in HIV RNA levels.66 Patients who mount a weak CTL response typically have a high set point and rapid progression of HIV disease; in contrast, patients with a strong CTL response have a low set point and slower disease progression [see Figure 9].® The strength and effectiveness of the T cell response are influenced by the human leukocyte antigen (HLA) genotype of the individual, with certain genotypes reportedly associated with different rates of disease progression; HLA-B27 and HLA-B57, in particular, have been strongly associated with long-term nonprogres-sion.67-69 The HIV CD8+ CTL response requires a highly coordinated action of multiple cells, including CD4+ helper T cells.
Shortly after acute HIV infection, HIV begins to preferentially destroy HIV-directed CD4+ helper T cells; this process impairs the critical interaction between host CD4+ T cells and CD8+ T cells and thus weakens the host CTL response.
Genetic variations in the host’s HIV coreceptors also may play a significant role in the initial progression of HIV disease, most notably with regard to the CCR5-A32 heterozygous mutation [see HIV Structure and Life Cycle, above] and the CCR2-64I mutation.50 Individuals with the CCR5-A32 or CCR2-64I mutation express coreceptors (or coreceptor levels) that are suboptimal for HIV binding, and thus, the level of HIV infection is depressed. Genetic differences between strains of HIV can also affect disease progression. HIV strains can be classified as either R5 or R4, depending on which cellular coreceptor the virus utilizes (CCR5 or CXCR4, respectively). This, in turn, influences whether the virus causes syncytia when grown in vitro.70 Syncytia-forming HIV strains, which are predominantly R4 (CXCR4-using) viruses, destroy CD4+ lymphocytes more effectively in vivo; their appearance correlates with a rate of CD4+ T cell decline that may be almost three times more rapid than that seen in persons with the nonsyncytium strains.70 Several reports have also described a small number of persons with very delayed disease progression who are infected with HIV strains containing particular sequence variations or deletions, such as absence of the regulatory gene nef. These genetic variations appear to render the virus less pathogenic.71,72 Finally, individuals with persistent coinfection with the flavivirus GB virus C (GBV-C) may exhibit slower rates of HIV disease progression.73 Proposed mechanisms for the interference of the HIV life cycle by GBV-C include a shift to a Th1 cytokine profile, downregulation of CCR5, an improved innate immune response to HIV, and decreased viral replication.
