HIV - FROM EPIDEMIOLOGY TO DIAGNOSIS

1.2 PATHOGENESIS AND DIAGNOSIS OF HIV INFECTION I. HIV as a retrovirus I.A Classification of the HIV virus The human immunodeficiency virus (HIV) is an enveloped RNA virus belonging to the lentivirus subfamily of retroviruses. HIV-1 is the predominant strain of the current pandemic. HIV-2, in distinction from HIV-1, is identified mainly in West Africa, and is closely related to simian immunodeficiency virus (SIV). The clinical manifestations of HIV-2 are similar to those of HIV-1 but progression is typically slower. The Retroviridae is classified into three subfamilies: a. Oncovirniae: examples are HTLV-I and HTLV-II, STLV-1 (Simian T Lymphocytic Virus type 1). They are associated with lymphoma or leukemia b. Lentiviridae: HIV-1, HIV-2, SIV (Simian Immunodeficiency Virus) c. Spumavirnae: this group of virus is found in animals and no disease association has been established HIV was identified as the causative agent of the acquired immunodeficiency syndrome (AIDS) in 1983-84, by three different laboratories and named initially as: a. Human T-lymphocytic virus type III (HTLV-III) by the National Cancer Institute1 b. Lymphadenopathy-associated virus (LAV) by the Pasteur Institute,2,3 and c. AIDS-related virus (ARV) by the University of California, San Francisco4 HIV-1 itself is mainly divided into the M (main) and O (outlier) groups. In addition, there are 10 subtypes or clades of group M: A, B, C, D, E, F, G, H, and J, some of which are actually recombinants of other forms. Gag and env sequences form the basis for classification. HIV subtyping may allow tracking of the epidemic to a certain extent
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

(Box 1.4). In 1998, a new isolate that defied classification into either M or O group was designated group N for new or non-M, non-O. The predominant clade of HIV in Hong Kong is not known.

I.B Structure and function As a retrovirus, HIV codes for reverse transcriptase, and is thus able to produce DNA from its native RNA. The mature virion is composed of a central core surrounded by a spherical lipid envelope that it acquires by budding from the surface of an infected cell. The core contains reverse transcriptase, integrase and protease in association with two strands of RNA. HIV has a long genome with at least 9 genes. They are: a. 2 regulatory genes: tat, rev b. 4 accessory genes: vif, vpu, vpr, nef
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

c. 3 structural genes: i. gag (inner core polypeptides): - p17, p24, p7, p9 ii. pol (viral enzymes): enzymes - reverse transcriptase, protease, integrase iii. env (envelop proteins) - gp 120, gp 41 I.C The HIV life cycle On entry, the HIV virus takes over the CD4 bearing cells for its own reproduction:6 a. Free virus and possibly virus-infected cells enter the body during initial infection b. Virus envelope glycoprotein (gp120) attaches avidly to CD4 receptors, with the aid of a coreceptor, CCR-5 or CXCR4 (HIV strains that utilize CCR5 are termed R5 viruses and those that utilize CXCR4 are termed X4 viruses) c. The envelope fuses with the native cell plasma membrane d. The inner core is removed, freeing the retroviral RNA e. Using its reverse transcriptase, the HIV initiates viral DNA synthesis, using its own RNA as template f. Once synthesized, the proviral DNA enters the nuclear cytoplasm and is integrated into the host cell's DNA by an enzyme called the integrase g. Retroviral synthesis is begun, directed by the cell's infected DNA h. New viral particles are produced by budding at the cell membrane i. Mature viral cores are produced through action of viral protease after budding j. The complete virus is extruded into the bloodstream Understanding the life cycle facilitates the development of drugs against HIV replication. For example, nucleoside reverse transcriptase inhibitors have been in use since 1987. In recent years, nonnucleoside reverse transcriptase inhibitors and protease inhibitors have also been developed. Possible candidates in the near future are the nucleotide reverse transcriptase inhibitors, integrase inhibitors and fusion inhibitors. II. Pathogenesis
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

II.A Establishment of infection On entry into a susceptible host through the mucosal route or blood stream, HIV transmission occurs by free virus entry or cell-to-cell transfer. The lymphoid organs have been implicated in the initial establishment of infection. Replication occurs in the infected cells in lymph nodes followed by systemic dissemination, which may result in systemic symptoms. II.B Host immune response The infected individual does mount specific immune responses against the HIV, as evidenced by the following phenomena: a. Neutralizing antibody response - Antibodies are developed. Yet only those that can effectively activate complement can neutralize the antigen. There is evidence that this response is evaded by HIV with its enormous rate of mutations b. Cytotoxic T lymphocyte (CTL) response - HIV-specific CD8+ cytotoxic T lymphocyte is developed early in the course of HIV infection. This is mediated through a MHC restricted mechanism. However, as the disease progresses, CTL is diminished. Interestingly, successful suppression of viral load by antiretroviral therapy is also followed by diminished CTL. One goal of current vaccine trials is to augment this response II.C Immune destruction As the disease progresses, the immune system is rendered progressively ineffective. As CD4 T lymphocytes (helper cells) are depleted by HIV infection, an overall lessening of immune function results. Thus HIV infection of CD4 cells destroys the very cells required to control the retrovirus. The precise mechanisms whereby CD4 cells are depleted remain controversial. Some possibilities7 are: a. Filling of all CD4 receptor sites - Not only do cells lose their function as a result, they become targets of immune surveillance by reason of the attached gp120 b. Syncytia formation - infected CD4 cells fuse with other uninfected cells to form giant multinucleated cells.
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

Syncytium-inducing variants generally emerge in the course of infection and predate rapid decline in CD4 count c. Apoptosis - also called programmed cell death, apoptosis may result from the cross-linking of CD4 by gp120antigp120 immune complexes. Thus CD4 may be lost without direct infection by the virus d. Autoimmunity - It has been shown that mice immunized with lymphocytes from another mouse strain develop antibodies against gp120. No HIV prior exposure was necessary.8 The corollary of this finding is that exposure to gp120 may also induce immunity against some component of the CD4 cell e. Cellular transfer of HIV - by macrophages as antigen-presenting cells The destruction of CD4 lymphocytes is staggering. In a war of attrition between CD4 cells and HIV, the half lives of CD4 and HIV are 1 to 2 days and < 6 hours respectively.9 A tenuous balance is maintained in the beginning of the infection. As time goes on, the number of CD4 cells progressively decreases. When the count falls below 200/uL, the likelihood of developing opportunistic infections significantly increases. II.D The roles of monocytes and macrophages Monocytes and macrophages are the scavengers of the immune system. HIV infection of these cells occurs either by attachment of the CD4 receptor or by macrophage phagocytosis of whole HIV. The monocyte-macrophage is relatively resistant to the cytopathic effects of the virus. Once within the macrophage, HIV remains undetectable by the body's immune surveillance system and may replicate freely. Thus the macrophage may serve as a reservoir for HIV. III. Diagnosis of HIV infection III.A The HIV antibody test HIV antibody detection is still the gold standard for diagnosis of HIV infection. The standard means of testing is to perform screening using the extremely sensitive but relatively less specific enzyme-linked immunosorbent assay (ELISA) test. In persons with positive ELISA, a confirmatory Western blot should be performed, which is the approach adopted in Hong Kong. The western blot is more time consuming and labor-intensive but is extremely
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

specific. As an alternative, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization recommended 2 to 3 ELISA/rapid tests for HIV diagnosis in resource limited settings, depending on the HIV prevalence of the community and symptomatology of the patient. Serum antibody appears most commonly 1-3 months after infection. This period between HIV inoculation and the detection of antibody is termed "window period". With modern technology, the window period can be shorter than one month. In most circumstances, a negative HIV antibody test at three months after a suspected exposure can safely exclude infection if no further risk exposure has occurred. In Hong Kong, HIV screening is available in both private and public health services. Western blot confirmation is offered by the Government Virus Laboratory to other laboratories in case of a positive screening result. III.B Detection of virus Detection of virus or its marker is clinically important, especially in: a. diagnosis during acute HIV infection; b. diagnosis of infants of HIV-infected mothers, who will continue to have maternal HIV antibody up to 18 months of age; and c. monitoring the progress of disease. Tests include viral culture, p24 assay, proviral DNA, and plasma HIV-RNA by PCR or bDNA (the viral load). Of these, only plasma HIV-RNA load is available as a standard assay in the public service. As a diagnostic tool, the test is sensitive but not specific, especially if the pretest probability is low.10 Nevertheless it will be useful in forming an early working diagnosis in primary HIV infection. Experts in HIV medicine should be consulted before requesting a test and in interpreting such result(s).

open in browser PRO version

Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

open in browser PRO version

Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

References 1. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLVIII) from patients with AIDS and at risk for AIDS. Science 1984;224:500-3. 2. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphocyte retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71. 3. Wain-Hobson S, Vartanian JP, Henry M, et al. LAV revisited: origins of the early HIV-1 isolates from Institut Pasteur. Science 1991;252:961-5. 4. Levy JA, Hoffman AD, Kramer SM, et al. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984;225:840-2. 5. Brodine SK, Mascola JR, McCutchan FE, et al. Genotypic variation and molecular epidemiology of HIV. Infect Med 1997;14(9):739-48. 6. Reese RE, Betts RF. A practical Approach to Infectious Diseases. 4th ed. Little, Brown & Co. 1996. 7. Stine GJ. The immunology of HIV disease/AIDS. In: AIDS Update 2000. New Jersey: Prentice Hal, 2000:12353. 8. Kion TA, Hoffmann GW. Anti-HIV and anti-anti-MHC antibodies in alloimmune and autoimmune mice. Science 1991;253:1138-40. 9. Ho DD, Neumann AU, Perelson AS et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV infection. Nature 1995;373:123-6. 10. Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a
open in browser PRO version
Are you a developer? Try out the HTML to PDF API

pdfcrowd.com

case series. Ann Intern Med 1999;130:37-9.

open in browser PRO version

Are you a developer? Try out the HTML to PDF API

pdfcrowd.com