1. HIV and AIDS Rough Draft Reading: Abbas, pages 258-266 Flaherty, pages 225-233
Overview
Acquired Immunodeficiency Syndrome (AIDS) is caused by infection with the Human Immunodeficiency Virus (HIV). AIDS develops as latent HIV becomes activated and destroys cells of the immune system, such as CD4+ T cells. The clinical course of HIV infection is characterized by several phases, culminating in immune deficiency. for the treatment of AIDS include: attachment and fusion inhibitors, reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.
The internal structure of HIV
Parham Chapter 3 cover page

2. Learning Objectives for Vaccine lecture part I • Describe the devastating impact that HIV-1 and HIV-2 have had throughout the world. • Describe the viral proteins, receptors and co-receptors involved in HIV entry into cells • List and describe the different steps associated with the life cycle of HIV • Explain the clinical significance of the high mutation rates associated with retroviruses • Compare and contrast latency with HIV reproduction

3. • Describe how opportunistic infections result from AIDS
Learning Objectives for Vaccine lecture part II • Describe the pathogenesis and clinical course of HIV disease
• Describe how opportunistic infections result from AIDS
• Describe the mechanism of action for the six classes of antiretroviral drugs used to treat HIV infections
• List the prototype for each of the six classes of antiretroviral drugs used to treat HIV
• Describe the importance of combinational therapy (HAART) in treating HIV infections
• Explain the difficulties associated with developing an effective vaccine for HIV

4. Acquired (secondary) immunodeficiencies
Abbas Fig Acquired (secondary) immunodeficiency. The table lists the most common causes of acquired immunodeficiency diseases and how they lead to defects in immune responses.  
Acquired Immunodeficiency Syndrome (AIDS) was first recognized as a distinct entity in the
1980s. HIV is closely related to the Simian immunodeficiency viruses (SIVs) that are found in monkeys and chimpanzees in equatorial Africa. Genetic sequencing suggests that a SIV virus may have crossed the species barrier and infected humans in approximately 1930, and subsequently became HIV-1. HIV-2 is a related strain that is believed to have crossed into humans sometime between 1955 and There are multiple subgroups of HIV-1 and HIV-2, referred to as clades, which are derived from a common ancestor virus.
AIDS is caused by infection with HIV. AIDS has become one of the most devastating afflictions in history. Of the estimated 34 million HIV- infected people worldwide, about 70% are in Africa and 20% in Asia. More than 30 million deaths are attributable to HIV/AIDS, with about 2 million deaths annually. Effective anti-retroviral drugs have been developed, but the infection continues to spread in parts of the world where these therapies are not widely available. Therefore, in some African countries, more than 30% of the population has HIV infection. HIV-1 is the predominant strain that has been transmitted in USA, whereas HIV-2 is the predominant strain in Africa
Abbas Fig. 12-6

5. Transmission of HIV Infection
Murray Medical Microbiology 4th Edition. Table 61-4.
HIV infection is typically acquired by sexual intercourse, sharing contaminated needles used by intravenous drug users, or transfusion of infected blood or blood products. HIV-2 is spread much more easily by heterosexual intercourse than HIV-1. Though some HIV-1 clades in USA have demonstrated heterosexual intercourse transmission (as described in the bottom of first column, Flaherty, page 215).
Table 61-4.
Murray Medical Microbiology 4th Edition.

6. Structure of HIV Abbas Fig 12–7A. Structure of HIV.
Abbas Fig 12–7A.    Structure of HIV. An HIV-1 virion is shown next to a T cell surface. HIV-1 consists of two identical strands of RNA (the viral genome) and associated enzymes, including reverse transcriptase, integrase, and protease, packaged in a cone-shaped core composed of the p24 capsid protein with a surrounding p17 protein matrix, all surrounded by a phospholipid membrane envelope derived from the host cell. Virally encoded envelope proteins (gp41 and gp120) bind to CD4 and chemokine receptors on the host cell surface.
Abbas Fig 12–7A.    Structure of HIV.

7. Genome of HIV
Presence of overlapping genes is common in viruses, which tend to have small and compact genomes
B, The HIV-1 genome consists of genes whose positions are indicated here as different-colored blocks. Some genes contain sequences that overlap with sequences of other genes, as shown by overlapping blocks, but are read differently by host cell RNA polymerase. Similarly shaded blocks separated by lines (tat, rev) indicate genes whose coding sequences are separated in the genome and require RNA splicing to produce functional messenger RNA. The major functions of the proteins encoded by different viral genes are listed. Students should be familiar with the importance of Long-terminal-repeats (LTR) that promote recombination of viral DNA with host chromosomes to establish latency. Students should also be familiar with the production of production of the envelope proteins (gp160 and gp41) from the env gene.

8. Attachment and membrane fusion of HIV
Flaherty Figure 26-3   Attachment and membrane fusion of human immunodeficiency virus (HIV). (From Abbas AK, Lichtman AH: Basic immunology, ed 3 [updated edition], Philadelphia, 2010, Saunders The life cycle of HIV infection begin with attachment of HIV virion to host cell through binding of gp120 to CD4 and a chemokine receptor (CXCR4 on T cells or CCR5 on macrophages). Macrophages and dendritic cells can also be infected by HIV. FYI, beyond scope of the course, yet some innate cells can express some levels of CD4, such as macrophages and dendritic cells, and that explains why they can be infected by HIV.
Flaherty Fig 26-3 

9. Life cycle of HIV
Abbas Fig 12–8.   Life cycle of human immunodeficiency virus (HIV-1). The sequential steps in HIV reproduction are shown, from initial infection of a host cell to release of a new virus particle (virion). For the sake of clarity, the production and release of only one new virion are shown. An infected cell actually produces many virions, each capable of infecting nearby cells, leading to spread of the infection. The steps associated with HIV infection consist of six main steps: 1) attachment of virion to host cell 2) membrane fusion permitting entry viral nucleic acid into cell 3) reverse transcriptase-mediated production of viral DNA 4) integration of viral DNA into the host chromosome. The integrated virus is called a polymerase. 5) expression of viral genes 6) production and budding of viral particles

10. TEM of both budding and released HIV-1
Photo by Alyne Harrison, Erskine Palmer, Paul Feorino (1984)

11. High mutation rate of HIV is due to permissive nature of reverse transcriptase -antigenic variation of gp120 & gp41 compromises ability -to make effective vaccine -ability of antibodies to limit spread of virus
Abbas Fig Evasion of humoral immunity by microbes. This table lists the principal mechanisms by which microbes evade humoral immunity, with illustrative examples. HIV, Human immunodeficiency virus. Antigenic variation of pathogens limits the effectiveness of vaccines. The inability to provide effective vaccine against the HIV virus serves as an example. Vaccines: The development of effective vaccines will likely be a major component of the strategy for control of HIV infection worldwide. A successful vaccine probably needs to induce an innate immune response, high titers of neutralizing antibodies, a strong T cell response, as well as mucosal immunity. It has proved difficult to achieve all these goals with current vaccination strategies. An additional challenge is the ability to protect against all subtypes of HIV. Early efforts focused on gp120 vaccines. These vaccines were largely unsuccessful because of the high rate of mutations in gp120. It will take years to judge the effectiveness of new vaccines in clinical trials.

12. Means of HIV Escape from the Immune System
Students should be familiar with this list. Antigenic drift is caused by the higher mutation rate of RNA-dependent-DNA polymerase activity of Reverse Transcriptase. Reverse transcriptases do not have proofreading ability, therefore have a much higher mutation rate in comparison to DNA polymerases.
Murray’s Medical Microbiology, 4th Edition. Table 61-3

13. Pathogenesis of AIDS
Figure    Pathogenesis of disease caused by human immunodeficiency virus (HIV). The development of HIV disease is associated with the spread of HIV from the initial site of infection to lymphoid tissues throughout the body. The immune response of the host temporarily controls acute infection but does not prevent establishment of chronic infection of cells in lymphoid tissues. Cytokines produced in response to HIV and other microbes serve to enhance HIV production and progression to acquired immunodeficiency syndrome (AIDS). CTLs, Cytotoxic T lymphocytes. A small fraction of patients control HIV infection without therapy. These individuals are often referred to as elite controllers or long-term non-progressors. There has been great interest in defining the genes that may protect these individuals, because elucidation of these genes could suggest novel therapeutic approaches. Some of these subjects inherit a deletion in the CCR5 chemokine receptor that compromises its ability to function as a co-receptor for viral entry.

14. Clinical course of HIV disease
Figure 12-10A.   Clinical course of HIV disease. A, Blood-borne virus (plasma viremia) is detected early after infection and may be accompanied by systemic symptoms typical of acute HIV syndrome. The virus spreads to lymphoid organs, but plasma viremia falls to very low levels (detectable only by sensitive reverse transcriptase–polymerase chain reaction assays) and stays this way for many years. CD4+ T cell counts steadily decline during this clinical latency period because of active viral replication and T cell destruction in lymphoid tissues. As the level of CD4+ T cells falls, there is increasing risk of infection and other clinical components of acquired immunodeficiency syndrome (AIDS). B, Magnitude and kinetics of immune responses, shown in arbitrary relative units. CTLs, Cytotoxic T lymphocytes.

15. Magnitude and kinetics of immune responses
Magnitude and kinetics of immune responses (shown in relatively arbitrary units)
Figure 12-10B.   Clinical course of HIV disease. A, B, Magnitude and kinetics of immune responses, shown in arbitrary relative units. CTLs, Cytotoxic T lymphocytes. (Reproduced with permission from Pantaleo G, Graziosi C, Fauci A: The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 328: , 1993.)
Abbas Fig. 12–10.   

16. Opportunistic pathogens associated with AIDS
Indicator diseases of AIDS Murray’s Medical Microbiology 4th Ed. Similar table found on Flaherty Box 26-1.

17. HAART (Highly active anti-retroviral therapy) - strategy of utilizing combinations of drugs to inhibit viral replication at different steps.
Raltegravir is the prototype integrase inhibitor (not included in table on right)
Table 49-2 Katzung & Trevor’s Pharmacology Examination & Board review 10th Ed. Be familiar with the prototypes of 5 subclasses of antiretroviral drug listed on left. Additionally, be familiar with Raltegravir, the prototype integrase inhibitor (not shown in table above). HAART (Highly active anti-retroviral therapy) is a treatment strategy that utilizes combinations of drug to inhibit viral replication at different steps. The use of HAART permits viral inhibition despite viral resistance to an individual therapeutic, as it is unlikely that an individual virion would obtain resistance to all anti-viral drugs simultaneously. HAART therapy typically entails combining different NRTIs combined with an anti-viral component of a separate class. At the present time, over 30 drugs have been approved by the FDA to treat HIV infections, recent updates are available on the following CDC website:
Table 49-2 Katzung & Trevor’s Pharmacology Examination & Board review 10th Ed.

18. Steps in HIV life cycle targeted by therapeutics
Maraviroc prevents attachment
Enfuvirtide prevents membrane fusion.
Therapeutics target different steps in the ife cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors. Attachment and fusion inhibitors prevent the initial interactions between the HIV and target cell membranes. Two fusion inhibitors are licensed in the United States: (1) Maraviroc prevents the binding of gp120 to the CCR5 co-receptor for HIV. It is most effective when used to treat individuals infected with macrophage-tropic HIV strains. However, it does not inhibit HIV attachment of CXCR4 lymphocyte-tropic HIV-1 strains. (2) Enfuvirtide is a synthetic 36-amino- acid segment from the HR2 region of gp41, which prevents the formation of a fusion protein necessary for membrane fusion.
Fig Katzung & Trevor Basic & Clinical Pharmacology 13th Ed.

19. Steps in HIV life cycle targeted by therapeutics
Raltegravir is an integrase inhibitor
Integrase Inhibitors: Integrase is an attractive drug target because integration of viral DNA into the host genome is critical to the infective process. Moreover, integrase has no functional analog in humans. Raltegravir is a non-toxic, selective integrase inhibitor currently licensed by the FDA. This drug acts by inhibiting single-strand transfer of viral DNA to the host genome.
Fig Katzung & Trevor Basic & Clinical Pharmacology 13th Ed.

20. Zidovudine (AZT) -an example of a NRTI
Flaherty Figure Normal deoxythymidine is on the right. Deoxythymidine is used normally by host cell for DNA synthesis. HIV virus also uses deoxythymidine for synthesis of viral DNA from viral RNA genome, using the viral enzyme reverse transcriptase. The Zidovudine nucleoside analogue on left inhibits reverse transcriptase extension of viral DNA due to a nitrogen group at the 3’ position (instead of the hydroxyl group) which is required for both DNA and RNA synthesis. Phosphodiester bonds formed during DNA or RNA synthesis require a 3’ hydroxyl (OH) group. The reverse transcriptase (RT) is a major target in anti-retroviral therapy. RT inhibitors are classified as nucleoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside reverse transcriptase inhibitors (NRTIs) include thymidine analogs (Zidovudine, also known as AZT) thymidine analogs and cytidine analogs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have different chemical structures, yet they are all highly specific to the HIV-1 RT. These drugs bind to the RT and inhibit RNA and DNA polymerase activity. Delavirdine is an example of NNTRI currently approved in the USA.

21. Indinavir-prototype protease inhibitor Protease inhibitors interfere with the proper maturation of HIV virions
Murray Medical Microbiology, Fig Protease Inhibitors: Indinavir is the prototype. These drugs prevent the cleavage of the large precursor HIV poly-proteins into active HIV proteins and enzymes. Protease inhibition results in disorganized capsid or matrix formation and the production of noninfectious viruses.
HIV protease is required for proper maturation of the HIV virion 
Murray Medical Microbiology, Fig