What is Hacking’s argument for entity realism?

According to Ian Hacking’s Entity Realism, unobservable entities that scientists carefully manipulate to study other phenomena are real. Although Hacking presents his case in an intuitive, attractive, and persuasive way, his argument remains elusive. I present five possible readings of Hacking’s argument: a no-miracle argument, an indispensability argument, a transcendental argument, a Vichian argument, and a non-argument. I elucidate Hacking’s argument according to each reading, and review their strengths, their weaknesses, and their compatibility with each othe

Vaccination with live attenuated simian immunodeficiency virus causes dynamic changes in intestinal CD4+CCR5+ T cells

<p>Abstract</p> <p>Background</p> <p>Vaccination with live attenuated SIV can protect against detectable infection with wild-type virus. We have investigated whether target cell depletion contributes to the protection observed. Following vaccination with live attenuated SIV the frequency of intestinal CD4+CCR5+ T cells, an early target of wild-type SIV infection and destruction, was determined at days 3, 7, 10, 21 and 125 post inoculation.</p> <p>Results</p> <p>In naive controls, modest frequencies of intestinal CD4+CCR5+ T cells were predominantly found within the LPL T_TrM-1and IEL T_TrM-2subsets. At day 3, LPL and IEL CD4+CCR5+ T_EMcells were dramatically increased whilst less differentiated subsets were greatly reduced, consistent with activation-induced maturation. CCR5 expression remained high at day 7, although there was a shift in subset balance from CD4+CCR5+ T_EMto less differentiated T_TrM-2cells. This increase in intestinal CD4+CCR5+ T cells preceded the peak of SIV RNA plasma loads measured at day 10. Greater than 65.9% depletion of intestinal CD4+CCR5+ T cells followed at day 10, but overall CD4+ T cell homeostasis was maintained by increased CD4+CCR5- T cells. At days 21 and 125, high numbers of intestinal CD4+CCR5- naive T_Ncells were detected concurrent with greatly increased CD4+CCR5+ LPL T_TrM-2and IEL T_EMcells at day 125, yet SIV RNA plasma loads remained low.</p> <p>Conclusions</p> <p>This increase in intestinal CD4+CCR5+ T cells, following vaccination with live attenuated SIV, does not correlate with target cell depletion as a mechanism of protection. Instead, increased intestinal CD4+CCR5+ T cells may correlate with or contribute to the protection conferred by vaccination with live attenuated SIV.</p

Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

Association between anti-HLA reactivity following vaccination with uninfected C8166 cells using different adjuvants and outcome of challenge.

<p>Virus infection status was determined by PCR for SIV<i>gag</i> proviral DNA and virus isolation (VI) from PBMC of macaques challenged with SIVmac₂₅₁32H (a) following vaccination with 4 doses of uninfected C8166 cells with Quil A adjuvant (group E) or with GMDP adjuvant (group F) (a) following vaccination with 2 doses of SIV infected C8166 cells (group C) or with uninfected C8166 cells (group D). Bar charts show the associated median fluorescence intensity (y axis) of serum samples for each macaque tested against HLA class I (red bars) and class II (green bars) bead sets (x axis). Background binding of pre-vaccination sera is shown as light red and light green for HLA class I and class II respectively. * indicates not tested, probe number refers HLA allele-specific bead sets.</p

Association between anti-HLA reactivity following vaccination with formalin-inactivated SIV and outcome of challenge.

<p>Virus infection status was determined by PCR for SIV<i>gag</i> proviral DNA and virus isolation (VI) from PBMC of macaques challenged with SIVmac₂₅₁32H (a) following vaccination with inactivated SIV with either 3×500 µg doses (group A) or 4×100 µg doses (group B). Bar charts show the associated median fluorescence intensity (y axis) of serum samples for each macaque tested against HLA class I (red bars) and class II (green bars) bead sets (x axis). Background binding of pre-vaccination sera is shown as light red and light green for HLA class I and class II respectively. * indicates not tested, probe number refers HLA allele-specific bead sets.</p

Infectivity neutralising activity against virus unrelated to vaccine.

<p>Neutralising antibody activity against SIVsmE660 propagated on human C8166 cells in sera from macaques immunised with uninfected C8166 cell vaccines (group E) in the absence (left panel) or presence (right panel) of complement. Pre-immune sera (black line) shows means of all animals with standard deviations. Dashed lines indicate unprotected animal.</p

Infectivity neutralising activity against virus propagated on discordant cell substrate.

<p>Neutralising antibody activity against SHIV_W61D propagated on either human C8166 cells (solid lines) or macaque HSC-F cells (dotted lines) in sera from macaques immunised with SIV-infected (J69; green lines) or uninfected C8166 cell (J73; purple lines) vaccines.</p