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Chapter 13 : Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival

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Abstract:

HIV pathogenesis reflects the various biologic properties of HIV and the host’s immune response to the virus. The differential expression of these two major components of HIV infection determines the final outcome: long-term survival or development of AIDS with its associated opportunistic infections and cancers. How these viral and immunological features of HIV pathogenesis influence survival from HIV infection becomes an important consideration. This chapter first discusses cofactors in HIV infection and disease progression. The pathogenic pathway, after the acute infection period, can be divided into three major phases: early period following acute virus infection, persistent period, and symptomatic period. One noteworthy observation is the loss of CD4+ T cells in the bowel of SIV-infected healthy sooty mangabeys similar to that noted in HIV infection. The chapter talks about high-risk HIV-exposed seronegative individuals, and diversity of viruses involved in transmission and infection. In addition to the studies on R5 versus X4 pathogenesis, several experiments have been initiated to determine if some HIV-1 subtypes distinguished by specific biologic and serologic features are associated with pathology in certain tissues. Three major tissues with potential virus subtypes are reviewed, but others could eventually include HIV-1 isolates isolated from the heart, lung, kidney, and endocrine organs.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13

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Figures

Image of Figure 13.1
Figure 13.1

Schematic diagram of events occurring after HIV infection. Prior to seroconversion, high levels of virus(—) can be detected in the blood (phase 1). Subsequently, this viremia is reduced to low levels (end of phase 1) and maintained with episodic release of varying amounts of virus over time (phase 2): Months to years later, concurrent with the onset of clinical symptoms, a second high level of viremia occurs and remains raised throughout the terminal period (i.e., development of AIDS) (phase 3). The CD4 cell number (....) decreases during acute (primary) infection (phase 1) and then returns to a level somewhat below normal. A slow decrease in CD4 cell count, estimated to be approximately 60 cells/μl per year (2401), occurs over time (the persistent period) (phase 2). Subsequently, in some individuals developing symptoms, a marked decrease in CD4 cell counts can be observed concomitant with reemergence of high levels of viremia (phase 3). The number of CD8 cells (- - -) rises during primary infection, as is commonly seen in viral infections. Their number then returns to just above normal and stays elevated until the final stages of disease. In contrast, the CD8 cell anti-HIV responses (-- — -- —) begin to decrease prior to or around the time of symptoms (late in phase 2) and then to decrease steadily as progression to disease occurs (phase 3). Modified from reference 2516 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.2
Figure 13.2

HIV replication permits genetic mutations to the virus. HIV, when replicating through different cells, mutates towards a strain that replicates rapidly, is more cyto-pathic, and can adapt to grow in various tissues such as the brain. Each replicative cycle can lead to up to 10 mutations (most of them lethal), but the surviving virions generally have a faster replication and a high level of virus replication.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.3
Figure 13.3

HIV-1 recovered early during infection from a relatively healthy individual shows very few cytopathic effects when inoculated onto normal peripheral blood mononu-clear cells. In contrast, HIV-1 isolated later from the same individual when he had AIDS shows the syncytium formation and balloon degeneration characteristic of virulent isolates ( Table 13.8 ). Reprinted from reference 2519 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.4
Figure 13.4

Replication of two isolates of HIV-1 recovered from the same individual over time. HIV-1(O), isolated early in the course of infection, replicates slowly and to low titer in the established HUT 78 T-cell line. In contrast, HIV-1 (Δ), recovered when the patient had AIDS, grows rapidly and to high titer in the same cells. These and other biologic differences between these two isolates have been used to distinguish viruses in culture as nonvirulent and virulent strains as well as slow/low and rapid/high strains (Table 7.8 and Figure 7.14).

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.5
Figure 13.5

CD8 cell anti-HIV activity in an HIV-infected individual monitored over time. In this subject, the loss of the CD8 cell response, reflected by the relative ability to suppress virus replication ( axis, left) decreases prior to a loss of CD4 cell number ( axis, right). Virus production (▲) resumes at time of reduced CD8 cell antiviral response. Modified from reference 2520 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.6
Figure 13.6

Balanced immunogenicity. In this model, sufficient noninfected or non-virus-releasing CD4 cells are present to make interleukin-2 (IL-2), which maintains the production of the CD8 cell antiviral factor (CAF) by CD8 cells. CAF, in turn, suppresses HIV production and prevents the loss of the CD4 cells and their function.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.7
Figure 13.7

Immune pathogenesis. CD4 cells produce cytokines such as interleukin-2 (IL-2) that maintain the production of the CD8 cell antiviral factor (CAF). CAF inhibits CD4 cell release of HIV. If an inhibitory event prevents IL-2 production by CD4 cells (pathway 1) or blocks CAF production by CD8 cells (pathway 2), HIV production takes place.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.8
Figure 13.8

Antigen-presenting cells (APC) (e.g., dendritic cells), through their expression of major histocompatibility complex (MHC) molecules and B7 proteins, help in the stimulation of CD4 and CD8 cell responses. The ultimate result is an increase in interleukin-2 (IL-2) production and IL-2 receptor (IL-2R) expression. In terms of HIV infection, this co-stimulation can lead to an increase in the CD8 cell noncytotoxic antiviral immune response with CAF production and thereby control of virus replication (255).

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.9
Figure 13.9

CD4 cell counts in long-term survivors and progressors. Over a 10-year period, CD4 cell counts remained within the normal range (shaded area) for long-term survivors but persistently decreased in progressors. Figure provided by E. Barker.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.10
Figure 13.10

Progression to AIDS with time. In the San Francisco city cohort, individuals known to be infected have been monitored since 1978. The results through 1995 show that it takes about 10 years for 50% of the individuals to develop AIDS; 69% of the infected subjects develop the disease within 14 years (545, 2597; S. Buchbinder, personal communication). Figure provided by S. Buchbinder.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.11
Figure 13.11

Suppression of HIV replication by CD8 cells. CD8 cells at different input ratios were added to acutely infected CD4 cells. The relative extent of suppression was determined. The smallest number of CD8 cells needed to suppress virus replication by more than 90% was determined. The strength of the CD8 cell response in long-term survivors was significantly higher than that in progressors ( = 0.001). Figure provided by E. Barker.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.12
Figure 13.12

Viral and immunologic events in the persistent clinically healthy stage (e.g., in long-term survivors). HIV infection of CD4 cells (step 1) is placed into a relatively latent state by the action of noncytotoxic CD8 cells and the CD8 cell antiviral factor (CAF) (~ ~) (step 2). This CD8 cell anti-HIV response is increased with the production of type 1 cytokines (e.g., interleukin-2 [IL-2]) secreted by TH1 CD4 cells (step 3). The type 1 cytokines also suppress the potential inhibitory effects of type 2 cytokines (produced by TH2 CD4 cells) on this control of HIV infection by CD8 cells (step 4). Modified from reference 2520 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.13
Figure 13.13

Events occurring in individuals progressing to disease (i.e., progressors). The events described in the legend to Figure 13.12 are changed by a predominant expression of the TH2 versus the TH1 cytokine response. Cytokines such as interleukin-4 (IL-4) and IL-10 (step 4) can suppress cytokine production by TH1 cells and thereby affect the CD8 cell antiviral activity. Moreover, these cellular factors can directly inhibit CD8 cell antiviral responses ( Figure 13.12 ). The result of the loss of CD8 cell antiviral activity is release of the HIV from latency and production of virus in lymph nodes and peripheral blood. These events lead to development of disease. Reproduced from reference 2520 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Image of Figure 13.14
Figure 13.14

Cellular immune responses in long-term survival: approaches for controlling HIV pathogenesis. Methods directed at increasing CD8 cell anti-HIV activity such as interleukin-2 (IL-2) therapy (e.g., increasing production of CD8 cell antiviral factor (CAF) or enhancement of type 1 (TH1) cellular responses would suppress HIV infection and maintain a long asymptomatic state. Administration of CAF, once purified, might also be beneficial. Modified from reference 2520 with permission.

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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References

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Tables

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Table 13.1

Potential cofactors in HIV infection and pathogenesis

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.2

Herpesviruses as cofactors in HIV infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.3

Potential effects of infectious agents on HIV replication in culture

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.4

Potential effect of microbial infections on HIV pathogenesis

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.5

Characteristics of HIV isolates associated with virulence in the host

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.6

Possible causes of reduced CD4 cell number and function

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.7

Steps involved in HIV infection and pathogenesis

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.8

Factors suggesting disease progression in HIV infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.9

Cellular genes that affect HIV-1 infection and AIDS progression

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.10

HLA association with HIV disease progression

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.11

Reported characteristics of long-term survivors of HIV infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.12

Factors influencing long-term survival

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.13

Observations on high-risk seronegative individuals that suggest HIV exposure and protection from infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.14

Reasons for R5 predominance during acute and primary infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.15

Potential reasons for a switch from R5 to X4 HIV phenotype during the course of infection

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13
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Table 13.16

Characteristics of HIV-1 isolates recovered from different tissues

Citation: Levy J. 2007. Overall Features of HIV Pathogenesis: Prognosis for Long-Term Survival, p 317-361. In HIV and the Pathogenesis of AIDS, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815653.ch13

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