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MEDICAL BIOLOGY: ON PNEUMOCYSTIC PNEUMONIA

The following points are made by C.F. Thomas, Jr. and A.H. Limper (New Engl. J. Med. 2004 350:2487):

1) Pneumocystis pneumonia remains the most prevalent opportunistic infection in patients infected with the human immunodeficiency virus (HIV).(1,2) First identified as a protozoan nearly 100 years ago and reclassified as a fungus in 1988, pneumocystis cannot be propagated in culture.(3-5) Few treatment options exist for patients with this pneumonia. The number of patients who are receiving chronic immunosuppressive medication or who have an altered immune system and are thus at risk for pneumocystis pneumonia is rapidly growing.(2)

2) The full identification and classification of pneumocystis took many decades. Pneumocystis organisms were first identified by Carlos Chagas (1879-1934) in the early 20th century, with the use of a guinea-pig model of trypanosome infection, and subsequently by Antonio Carinii, in infected rat lungs.(4,5) Both investigators believed they had identified new forms of trypanosomes. Several years later, however, the Delanoes (3), a husband and wife team, recognized that Chagas and Carinii had identified a new species with a unique tropism for the lung; hence, the new species was named Pneumocystis carinii. neumocystis was initially misclassified as a protozoan on the basis of the morphologic features of the small trophic form, the larger cyst form, the development of up to eight progeny within the cyst, and the rupture of the cyst to release new trophic forms. In 1988, an analysis of the small rRNA subunit from pneumocystis pneumonia established a phylogenetic linkage to the fungal kingdom, and all subsequent genomic information has corroborated pneumocystis's home within the ascomycetous fungi.

3) Pneumocystis organisms have been identified in virtually every mammalian species. In humans, serologic surveys have shown nearly universal seropositivity to pneumocystis in tested populations by two years of age. Pneumocystis organisms encompass a family of organisms that have a range of genetic characteristics and that are host-specific. For example, the pneumocystis that infects humans, which was recently renamed P. jirovecii, cannot infect the rat, and vice versa. The reason for this stringent host specificity is unclear. The use of binomial nomenclature for human pneumocystis may be of less importance currently, given that visualization of the organism is required for the diagnosis of pneumonia. When PCR has been applied to pneumocystis pneumonia in humans, only P. jirovecii has been found, and for that reason, specifying the name of the species will become important only if additional species of pneumocystis are found to infect humans.

4) The major obstacle to studying pneumocystis is the inability to achieve sustained propagation of the organism outside the host lung. Many investigators have attempted to cultivate pneumocystis using a variety of techniques, but none have been successful. Cell-free systems that use media preparations for growing protozoa, bacteria, and fungi and tissue-culture systems in which a variety of cell lines are used have not been successful. Attempts to simulate the intraalveolar environment and to supplement media with numerous additives, such as surfactant, lung homogenates, or various chemical compounds, have also proved unhelpful. Until the organism can be cultivated in vitro, the infected-animal model of pneumocystis pneumonia will remain the source of organisms for study.

References (abridged):

1. HIV/AIDS surveillance supplemental report. Vol. 9. No. 3. Atlanta: Centers for Disease Control and Prevention, 2003:1-20

2. Sepkowitz KA. Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis 2002;34:1098-1107. [Erratum, Clin Infect Dis 2002;34:1293.]

3. Delanoe P, DelanoÙ M. Sur les rapports des kystes de Carini du poumon des rats avec le Trypanosoma Lewisi. C R Acad Sci 1912;155:658-60

4. Chagas C. Nova tripanozomiaze humana: estudo sobre a morfolojia e o evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz 1909;1:159-218

5. Carinii A. Formas de eschizogonia do Trypanozoma lewisi. Commun Soc Med Sao Paolo 1910;16:204

New Engl. J. Med. http://www.nejm.org

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EPIDEMIOLOGY: ON THE ORIGINS OF HIV

The following points are made by J. Stebbing et al (New Engl. J. Med. 2004 350:1872):

1) The worldwide dissemination of human immunodeficiency virus (HIV) over the past four decades is one of the most catastrophic examples of the emergence, transmission, and propagation of a microbial genome.(1) We now know that the cellular and anatomical sites of HIV replication influence the course of the infection, the ability of antiretroviral therapy to reduce viremia, and the establishment of the viral reservoir. This highly mutable virus inserts its genome into the genomes of crucially important cells of the host and, despite therapy, maintains a reservoir of latent HIV within the body.(2) The virus has a predilection for activated HIV-specific CD4+ T cells, although other cells are also susceptible to the virus. This tropism for particular cells is determined mainly by cellular receptors to which HIV attaches in order to enter cells.

2) The earliest documented case of HIV infection in humans was identified in a sample of serum from Kinshasa (Democratic Republic of Congo) that was stored in 1959.(3) On the basis of the HIV type 1 (HIV-1) sequences obtained from this and numerous other, more recent isolates, it has been estimated that the main (M) group of HIV-1 strains diversified in humans in about 1931 (95 percent confidence interval, 1911 to 1941).(4) Similarly, the most recent common ancestors of HIV type 2 (HIV-2) subtypes have been dated to the 1940s.(5)

3) There is persuasive evidence that HIV-1 came to humans from the chimpanzee (Pan troglodytes), which harbors the related simian immunodeficiency virus (SIVcpz) and lives in central Africa. HIV-2, whose DNA has 40 to 60 percent homology with HIV-1 DNA, originated from the SIVsm of the sooty mangabey (Cercocebus atys) monkeys of coastal West Africa, from Senegal to the Ivory Coast, the endemic epicenter of HIV-2. In these areas, nonhuman primates are kept as pets and butchered for food, suggesting routes of transmission -- monkey and ape to human -- that are in accord with phylogenetic data implying cross-species infection. Estimates of when HIV was introduced into the human population, on the basis of a molecular clock and the distribution of SIV genomic sequences among the chimpanzees of central Africa, render it highly improbable that contaminated poliovirus vaccines were the source of HIV.

4) It is striking that in all known instances of infection of the natural primate host of SIV, neither a disease resembling the acquired immunodeficiency syndrome (AIDS) nor a profound depletion of CD4+ T cells develops, despite the presence of very high viral loads. In contrast, transmission of SIV to unnatural hosts, such as the rhesus macaque (Macaca mulatta) or humans, causes a progressive loss of CD4+ T cells and a high degree of susceptibility to opportunistic infections. The importance of this point cannot be overstated and must surely lie at the core of the pathogenic mechanisms of HIV, which is in effect a zoonotic infection. It is unclear why SIV infection of its natural hosts fails to cause disease, but recent studies have shown that SIV does not elicit the prominent T-cell activation that is seen in chronic HIV infection. Other studies that analyzed polymorphisms in major-histocompatibility-complex genes suggest that present-day animals, which have SIV infection but no disease, may in fact represent the survivors of an ancient retroviral pandemic.

References (abridged):

1. Ho DD, Huang Y. The HIV-1 vaccine race. Cell 2002;110:135-138

2. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003;9:727-728

3. Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 1998;391:594-597

4. Korber B, Muldoon M, Theiler J, et al. Timing the ancestor of the HIV-1 pandemic strains. Science 2000;288:1789-1796

5. Lemey P, Pybus OG, Wang B, Saksena NK, Salemi M, Vandamme AM. Tracing the origin and history of the HIV-2 epidemic. Proc Natl Acad Sci U S A 2003;100:6588-6592

New Engl. J. Med. http://www.nejm.org

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MEDICAL BIOLOGY: ON HIV DRUG RESISTANCE

The following points are made by F. Clavel and A.J. Hance (New Engl. J. Med. 2004 350:1023):

1) The use of combinations of antiretroviral drugs has proven remarkably effective in controlling the progression of human immunodeficiency virus (HIV) disease and prolonging survival,(1) but these benefits can be compromised by the development of drug resistance.(2,3) Resistance is the consequence of mutations that emerge in the viral proteins targeted by antiretroviral agents. In the US, as many as 50 percent of patients receiving antiretroviral therapy are infected with viruses that express resistance to at least one of the available antiretroviral drugs.(4) Consequently, the transmission of drug-resistant strains is also a growing concern.(5) Because drug-resistant HIV often exhibits resistance to several classes of antiretroviral drugs and because cross-resistance between drugs within a class is frequent, the emergence of resistance always complicates further efforts to control viral replication.

2) The drugs currently used to treat HIV type 1 (HIV-1) infection belong to four distinct classes: nucleoside and nucleotide analogues, which act as DNA-chain terminators and inhibit reverse transcription of the viral RNA genome into DNA, a crucial event occurring at an early stage of the viral life cycle; nonnucleoside reverse-transcriptase inhibitors, which bind and inhibit reverse transcriptase, the viral enzyme that conducts reverse transcription; protease inhibitors, which target the viral protease, the enzyme required for the cleavage of precursor proteins (gag and gag-pol), permitting the final assembly of the inner core of viral particles; and entry inhibitors, which block the penetration of HIV virions into their target cells. Combinations of antiretroviral drugs are now used for the treatment of HIV infection -- so-called highly active antiretroviral therapy (HAART). Current HAART regimens generally comprise three antiretroviral drugs, usually two nucleoside analogues and either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor. The use of agents from different classes is instrumental in controlling the development of resistance, but whereas some drug combinations have been shown to be antagonistic, there is no evidence that any combinations of currently available drugs are strongly synergistic in vitro.

3) Two concepts are important to an understanding of the development of drug resistance. First, HIV infection is characterized by high levels of virus production and turnover. In most untreated patients, the total number of productively infected cells in the lymphoid tissue has been estimated to be approximately 10^(7) to 10^(8) cells. During the chronic phase of HIV infection, this number is relatively stable, reflecting the balance between the infection of new target cells and their clearance. Because the half-life of infected cells is remarkably short (one to two days), the maintenance of this steady state requires that HIV infect new target cells at a very high rate. Second, the viral population in an infected person is highly heterogeneous. The reverse transcription of viral RNA into DNA is notoriously prone to error, introducing on average one mutation for each viral genome transcribed. Most of these errors are base substitutions, but duplications, insertions, and recombination can also occur. The high rate of HIV infection, combined with the high mutation rate that occurs during each cycle of infection, ensures that patients have a complex and diverse mixture of viral quasispecies, each differing by one or more mutations.

References (abridged):

1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-860

2. DeGruttola V, Dix L, D'Aquila R, et al. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antivir Ther 2000;5:41-48

3. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999;282:2220-2226

4. Richman D, Bozette S, Morton S, et al. The prevalence of antiretroviral drug resistance in the US. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, December 16-19, 2001. Washington, D.C.: American Society for Microbiology, 2001

5. Yerly S, Kaiser L, Race E, Bru JP, Clavel F, Perrin L. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet 1999;354:729-733

New Engl. J. Med. http://www.nejm.org

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